Clinical trial NCT01374906: Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing's Disease
Official title: A Randomized, Double-blind, Multicenter, Phase III Study to Evaluate the Efficacy and Safety of Pasireotide LAR in Patients With Cushing's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cushing's Disease
Keywords: SOM230
Cushing's Disease
Mean Urinary Free Cortisol
Pasireotide
Pasireotide LAR
Pasireotide long-acting release
secondary hypercortisolism
secondary hypercorticism
Itsenko-Cushing disease
increased secretion of adrenocorticotropic hormone (ACTH)
hyperpituitarism
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-06-16
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, double-blind, multicenter, phase III study to evaluate the safety and efficacy of 2 dosing regiments of Pasireotide long acting release (LAR) in patients with Cushing's disease.


Eligibility criteria: Inclusion Criteria:

* Karnofsky performance status ≥ 60 (i.e. requires occasional assistance, but is able to care for most of their personal needs)
* For patients on medical treatment for Cushing's disease the following washout periods must be completed before screening assessments are performed

  * Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week
  * Pituitary directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPARγ agonists (rosiglitazone or pioglitazone): 4 weeks
  * Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks
  * Octreotide (immediate release formulation): 1 week

Exclusion Criteria:

* Patients who are considered candidates for surgical treatment at the time of study entry
* Patients who have received pituitary irradiation within the last ten years prior to visit 1
* Patients who have had any previous pasireotide treatment
* Patients who have been treated with mitotane during the last 6 months prior to Visit 1
* Diabetic patients on antihyperglycemic medications with poor glycemic control as evidenced by HbA1c \>8%
* Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF \>470 ms, hypokalemia, uncontrolled hypothyroidism, family history of long QT syndrome, or concomitant medications known to prolong QT interval
* Female patients who are pregnant or lactating, or are of childbearing potential (defined as all women physiologically capable of becoming pregnant) and not practicing an effective method of contraception/birth control. Sexually active males must use a condom during intercourse while taking the drug and for 2 months after the last dose of study drug and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Primary outcomes:
measure: Percentage Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 Regardless of Dose Titration
timeFrame: Month 7
Secondary outcomes:
measure: Percentage of Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 and Had Not Had a Dose Increase at Month 4
timeFrame: Month 7
measure: Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline
timeFrame: baseline, Month 7 (M7), Month 12 (M12), Month 24 (M24) , Month 36 (M36)
measure: Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline
timeFrame: M7, M12, M24, M36
measure: Percentage of Patients Who Attain mUFC ≤ 1.0 x ULN
timeFrame: M7, M12, M24, M36
measure: Percentage of Patients Who Attain mUFC ≤1.0 x ULN or Have at Least 50 % Reduction From Baseline in mUFC
timeFrame: M7, M12, M24, M36
measure: Percentage of Patients Who Are Controlled Responders (mUFC ≤ 1.0 xULN) on at Least 4 of the 7 mUFC Assessments by Month 7 & on at Least 7 of the 12 mUFC Assessments by Month 12.
timeFrame: Month 7, Month 12
measure: Percentage of Patients With Uncontrolled Response at Month 7 & Month 12 Within the Subset of Patients Who Had Uncontrolled Response at a) Months 1 and 2; b) Months 1, 2, and 3
timeFrame: Month 7, Month12
measure: Percent of Participants Attaining a mUFC ≤ 1.0 x ULN or at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points
timeFrame: Momth 7, Month 12
measure: Percent of Participants Attaining a Duration of Controlled or Partially Controlled Response at Indicated Time Points
timeFrame: Month 6, 12, 18
measure: Percentage Change From Baseline on Plasma Adrenocorticotropic Hormone (ACTH) Over Time
timeFrame: Months 7, 12, 24 & 36
measure: Percentage Change From Baseline on Serum Cortisol Over Time
timeFrame: Months 7, 12, 24 & 36
measure: Actual Change From Baseline in Clinical Signs Over Time: Blood Pressure
timeFrame: Month 7
measure: Actual Change From Baseline in Clinical Signs Over Time: Body Mass Index (BMI)
timeFrame: Month 7
measure: Actual Change From Baseline in Clinical Signs Over Time: Weight
timeFrame: Month 7
measure: Actual Change From Baseline in Clinical Signs Over Time: Body Composition: Region
timeFrame: Month 7
measure: Actual Change From Baseline in Clinical Signs Over Time: Waist Circumference
timeFrame: Month 7
measure: Actual Change From Baseline in Clinical Signs Over Time: Cholesterol & Triglycerides
timeFrame: Month 7
measure: Percentage Change From Baseline in Clinical Signs Over Time
timeFrame: Month 7
measure: Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs
timeFrame: Month 7
measure: Percentage of Participants That Attained a Mean Urinary Free Cortisol (mUFC) <= 1.0 x Upper Limit of Normal (ULN) at Month 7 Regardless of Dose Up-titration at Month 4.
timeFrame: Month 7
measure: Percentage of Patients That Attain a Reduction of at Least 50% in mUFC From Baseline
timeFrame: Months 7, 12, 24 & 36
measure: Percent of Participants Attaining a Time to First Achievement of at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points
timeFrame: every month in the core phase and every 3 months in the extension phase) up to and including the cut-off date for the Month 12 CSR (10-Nov-2015)
measure: Percent of Participants With a Duration of at Least 50% Reduction in mUFC From Baseline at Indicated Time Points
timeFrame: Months 6, 12 & 18
measure: Pharmacokinetic (PK) Parameter: Ctrough
timeFrame: Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337
measure: Pharmacokinetic (PK) Parameter: Cmax
timeFrame: Days 22, 106, 190
measure: Actual Change in Standardized Score of Cushing's Disease HRQoL (CushingQOL) Score From Baseline
timeFrame: Months 7, 12, 24 & 36
measure: Actual Change in SF-12v2 Score From Baseline - Mental Component Summary
timeFrame: Months 7, 12 & 24
measure: Actual Change in SF-12v2 Score From Baseline - Physical Component Summary
timeFrame: Months 7, 12 & 24
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: ClinTriCo
state: Arizona
city: Los Angeles
country: United States
facility: University of California at Los Angeles UCLA Tiverton
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Medical Center LA Biomed
state: California
city: Atlanta
country: United States
facility: Emory University School of Medicine/Winship Cancer Institute G2304 - C2301
state: Georgia
city: Baltimore
country: United States
facility: Pituitary Center, Division of Endocrinology SC
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center SC-2
state: Michigan
city: New York
country: United States
facility: Mount Sinai School of Medicine Mt. Sinai Medical Center
state: New York
city: Portland
country: United States
facility: Oregon Health & Sciences University DeptofOregonHealth&Sciences(2)
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania - Clinical Studies Unit Unniv SC
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center CSOM230G2304
state: Tennessee
city: Seattle
country: United States
facility: Swedish Medical Center Swedish
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin MCW 2
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Edegem
country: Belgium
facility: Novartis Investigative Site
state: Antwerpen
city: Jette
country: Belgium
facility: Novartis Investigative Site
state: Brussel
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Fortaleza
country: Brazil
facility: Novartis Investigative Site
state: CE
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Ribeirao Preto
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Halifax
country: Canada
facility: Novartis Investigative Site
state: Nova Scotia
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Sherbrooke
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Beijing
country: China
facility: Novartis Investigative Site
state: Beijing
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Besancon cedex
country: France
facility: Novartis Investigative Site
city: Caen Cedex9
country: France
facility: Novartis Investigative Site
city: Le Kremlin Bicetre
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Marseille Cédex 5
country: France
facility: Novartis Investigative Site
city: Pessac Cedex
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Germering
country: Germany
facility: Novartis Investigative Site
city: Wurzburg
country: Germany
facility: Novartis Investigative Site
city: Mumbai
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Vellore
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Petach Tikva
country: Israel
facility: Novartis Investigative Site
city: Ancona
country: Italy
facility: Novartis Investigative Site
state: AN
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Maebashi city
country: Japan
facility: Novartis Investigative Site
state: Gunma
city: Sapporo-city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Kobe-city
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Nankoku-city
country: Japan
facility: Novartis Investigative Site
state: Kochi
city: Kyoto-city
country: Japan
facility: Novartis Investigative Site
state: Kyoto
city: Suita-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Bunkyo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Minato-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Jesus Maria
country: Peru
facility: Novartis Investigative Site
state: Lima
city: Miraflores
country: Peru
facility: Novartis Investigative Site
state: Lima
city: Gdansk
country: Poland
facility: Novartis Investigative Site
city: Poznan
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: St.- Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Alzira
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Diskapi / Ankara
country: Turkey
facility: Novartis Investigative Site
state: Ankara
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Salford
country: United Kingdom
facility: Novartis Investigative Site
state: Manchester
city: Norwich
country: United Kingdom
facility: Novartis Investigative Site
city: Sheffield
country: United Kingdom
facility: Novartis Investigative Site
city: Southampton
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Lacroix A, Bronstein MD, Schopohl J, Delibasi T, Salvatori R, Li Y, Barkan A, Suzaki N, Tauchmanova L, Ortmann CE, Ravichandran S, Petersenn S, Pivonello R. Long-acting pasireotide improves clinical signs and quality of life in Cushing's disease: results from a phase III study. J Endocrinol Invest. 2020 Nov;43(11):1613-1622. doi: 10.1007/s40618-020-01246-0. Epub 2020 May 8.
citation: Newell-Price J, Pivonello R, Tabarin A, Fleseriu M, Witek P, Gadelha MR, Petersenn S, Tauchmanova L, Ravichandran S, Gupta P, Lacroix A, Biller BMK. Use of late-night salivary cortisol to monitor response to medical treatment in Cushing's disease. Eur J Endocrinol. 2020 Feb;182(2):207-217. doi: 10.1530/EJE-19-0695.
citation: Fleseriu M, Petersenn S, Biller BMK, Kadioglu P, De Block C, T'Sjoen G, Vantyghem MC, Tauchmanova L, Wojna J, Roughton M, Lacroix A, Newell-Price J. Long-term efficacy and safety of once-monthly pasireotide in Cushing's disease: A Phase III extension study. Clin Endocrinol (Oxf). 2019 Dec;91(6):776-785. doi: 10.1111/cen.14081. Epub 2019 Oct 1.
citation: Lacroix A, Gu F, Gallardo W, Pivonello R, Yu Y, Witek P, Boscaro M, Salvatori R, Yamada M, Tauchmanova L, Roughton M, Ravichandran S, Petersenn S, Biller BMK, Newell-Price J; Pasireotide G2304 Study Group. Efficacy and safety of once-monthly pasireotide in Cushing's disease: a 12 month clinical trial. Lancet Diabetes Endocrinol. 2018 Jan;6(1):17-26. doi: 10.1016/S2213-8587(17)30326-1. Epub 2017 Oct 12.
citation: Silverstein JM. Hyperglycemia induced by pasireotide in patients with Cushing's disease or acromegaly. Pituitary. 2016 Oct;19(5):536-43. doi: 10.1007/s11102-016-0734-1.