Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing's Disease

Cushing's Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01374906
• Other study ID #: CSOM230G2304
• Secondary ID: 2009-011128-70
• Status: Completed
• Phase: Phase 3
• Start date: November 4, 2011
• Est. completion date: December 21, 2016

Study information

• Verified date: April 2018
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 150
• Est. completion date: December 21, 2016
• Est. primary completion date: December 21, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 PPAR? 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

Related Conditions & MeSH terms

• ACTH-Secreting Pituitary Adenoma
• Cushing's Disease
• Pituitary ACTH Hypersecretion

Intervention

Drug:
• pasireotide LAR
Pasireotide long-acting was administered as an intra-muscular depot intragluteal injection once every 28 days (±2 days). Patients were administered pasireotide long-acting 10 mg or 30 mg for four months, followed by either continuation of the starting dose, or dose up-titration (if mUFC was still >1.5xULN unless titration was precluded by safety reasons).
• SOM230 LAR 30 mg
starting dose of 30 mg i.m. administered once every 28 days for 4 months, followed by dose up-titration or continuation of starting dose.
• SOM230 LAR 10 mg
starting does of SOM230 LAR 10 mg i.m. administered once every 28 days for 4 months, followed by dose up-titration or continuation of the starting dose.

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Jette	Brussel
Belgium	Novartis Investigative Site	Leuven
Brazil	Novartis Investigative Site	Fortaleza	CE
Brazil	Novartis Investigative Site	Ribeirao Preto	SP
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Halifax	Nova Scotia
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Sherbrooke	Quebec
China	Novartis Investigative Site	Beijing	Beijing
China	Novartis Investigative Site	Chengdu	Sichuan
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shanghai
France	Novartis Investigative Site	Besancon cedex
France	Novartis Investigative Site	Caen Cedex9
France	Novartis Investigative Site	Le Kremlin Bicetre
France	Novartis Investigative Site	Lille Cedex
France	Novartis Investigative Site	Marseille Cédex 5
France	Novartis Investigative Site	Pessac Cedex
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Germering
Germany	Novartis Investigative Site	Wurzburg
India	Novartis Investigative Site	Mumbai	Maharashtra
India	Novartis Investigative Site	New Delhi
India	Novartis Investigative Site	Vellore	Tamil Nadu
Israel	Novartis Investigative Site	Petach Tikva
Italy	Novartis Investigative Site	Ancona	AN
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Padova	PD
Japan	Novartis Investigative Site	Bunkyo-ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka city	Fukuoka
Japan	Novartis Investigative Site	Kobe-city	Hyogo
Japan	Novartis Investigative Site	Kyoto-city	Kyoto
Japan	Novartis Investigative Site	Maebashi city	Gunma
Japan	Novartis Investigative Site	Minato-ku	Tokyo
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Nankoku-city	Kochi
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Sapporo-city	Hokkaido
Japan	Novartis Investigative Site	Shinjuku-ku	Tokyo
Japan	Novartis Investigative Site	Suita-city	Osaka
Netherlands	Novartis Investigative Site	Rotterdam
Peru	Novartis Investigative Site	Jesus Maria	Lima
Peru	Novartis Investigative Site	Miraflores	Lima
Poland	Novartis Investigative Site	Gdansk
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Wroclaw
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	St.- Petersburg
Spain	Novartis Investigative Site	Alzira	Comunidad Valenciana
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Sevilla	Andalucia
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Turkey	Novartis Investigative Site	Diskapi / Ankara	Ankara
Turkey	Novartis Investigative Site	Istanbul	TUR
Turkey	Novartis Investigative Site	Izmir
United Kingdom	Novartis Investigative Site	Norwich
United Kingdom	Novartis Investigative Site	Salford	Manchester
United Kingdom	Novartis Investigative Site	Sheffield
United Kingdom	Novartis Investigative Site	Southampton
United States	University of Michigan Comprehensive Cancer Center SC-2	Ann Arbor	Michigan
United States	Emory University School of Medicine/Winship Cancer Institute G2304 - C2301	Atlanta	Georgia
United States	Pituitary Center, Division of Endocrinology SC	Baltimore	Maryland
United States	University of California at Los Angeles UCLA Tiverton	Los Angeles	California
United States	Medical College of Wisconsin MCW 2	Milwaukee	Wisconsin
United States	Vanderbilt University Medical Center CSOM230G2304	Nashville	Tennessee
United States	Mount Sinai School of Medicine Mt. Sinai Medical Center	New York	New York
United States	University of Pennsylvania - Clinical Studies Unit Unniv SC	Philadelphia	Pennsylvania
United States	ClinTriCo	Phoenix	Arizona
United States	Oregon Health & Sciences University DeptofOregonHealth&Sciences(2)	Portland	Oregon
United States	Swedish Medical Center Swedish	Seattle	Washington
United States	Harbor-UCLA Medical Center LA Biomed	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Canada,  China,  France,  Germany,  India,  Israel,  Italy,  Japan,  Netherlands,  Peru,  Poland,  Russian Federation,  Spain,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage Participants That Attained a mUFC = 1.0 x ULN at Month 7 Regardless of Dose Titration	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. Patients who discontinued before month 4 evaluations classed as non-responders. For patients missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value.	Month 7
Secondary	Percentage of Participants That Attained a mUFC = 1.0 x ULN at Month 7 and Had Not Had a Dose Increase at Month 4	Percentage of participants that attain a mUFC = 1.0×ULN at Month 7 and had not had a dose increase at Month 4. Patients who had a dose increase prior to Month 7 were counted as non-responders in this analysis.; Patients who discontinued before month 4 evaluations classed as non-responders. For patients missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value.; A responder was defined as a patient who attains mUFC =1.0 X ULN and had not had a dose increase at Month 4.	Month 7
Secondary	Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline	Actual change in mUFC (nmol/24h) from baseline by randomized groups.	baseline, Month 7 (M7), Month 12 (M12), Month 24 (M24) , Month 36 (M36)
Secondary	Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline	Percentage change in mUFC (nmol/24h) from baseline by randomized groups.	M7, M12, M24, M36
Secondary	Percentage of Patients Who Attain mUFC = 1.0 x ULN	Controlled responder: mUFC = 1.0×ULN by randomized groups.	M7, M12, M24, M36
Secondary	Percentage of Patients Who Attain mUFC =1.0 x ULN or Have at Least 50 % Reduction From Baseline in mUFC	Controlled responder: mUFC = 1.0×ULN. Partially controlled responder: at least 50% reduction in mUFC from Baseline, and mUFC >1.0×ULN.	M7, M12, M24, M36
Secondary	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.	Percentage of patients with mUFC = 1.0 x ULN at a minimum of 4 months up to and including Month 7, and at a minimum of 7 months up to and including Month 12 by randomized groups.	Month 7, Month 12
Secondary	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	Percentage of patients with mUFC > 1.0 xULN at Month 7 and Month 12 within the subset of patients who were uncontrolled at a) Months 1 & 2, b) Months 1, 2, & 3 by randomized groups.	Month 7, Month12
Secondary	Percent of Participants Attaining a mUFC = 1.0 x ULN or at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points	Time to first achievement of attaining a mUFC = 1.0 x ULN or at least a 50% reduction in mUFC from baseline by randomized groups.	Momth 7, Month 12
Secondary	Percent of Participants Attaining a Duration of Controlled or Partially Controlled Response at Indicated Time Points	Duration of controlled or partially controlled response is defined as the period starting from the date of patient's first normalization (mUFC= 1.0 x ULN) or at least 50% reduction from baseline up to the date when the patient's mUFC >1.0 x ULN and the reduction from baseline falls to less than 50% for the first time.	Month 6, 12, 18
Secondary	Percentage Change From Baseline on Plasma Adrenocorticotropic Hormone (ACTH) Over Time	Percentage change in ACTH (pmol/L) from Baseline by randomized groups.	Months 7, 12, 24 & 36
Secondary	Percentage Change From Baseline on Serum Cortisol Over Time	Percentage change in serum cortisol (nmol/L) from Baseline by randomized groups.	Months 7, 12, 24 & 36
Secondary	Actual Change From Baseline in Clinical Signs Over Time: Blood Pressure	Change in blood pressure measurements from Baseline	Month 7
Secondary	Actual Change From Baseline in Clinical Signs Over Time: Body Mass Index (BMI)	Change in BMI measurements from Baseline	Month 7
Secondary	Actual Change From Baseline in Clinical Signs Over Time: Weight	Change in weight measurements from Baseline	Month 7
Secondary	Actual Change From Baseline in Clinical Signs Over Time: Body Composition: Region	Change in body composition: region measurements from Baseline	Month 7
Secondary	Actual Change From Baseline in Clinical Signs Over Time: Waist Circumference	Change in waist circumference measurements from Baseline	Month 7
Secondary	Actual Change From Baseline in Clinical Signs Over Time: Cholesterol & Triglycerides	Change in parameter measurements: cholesterol & triglycerides from Baseline	Month 7
Secondary	Percentage Change From Baseline in Clinical Signs Over Time	Percentage change in parameter measurements: blood pressure, body mass index, waist circumference, fasting serum lipid profile, weight, bone density and body composition (examined by DXA scan) from Baseline	Month 7
Secondary	Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs	This includes patients with improvements in symptoms from baseline. Clinical signs over time include: facial rubor, fat pads, hirsutism, striae, (via photographs by a second local physician who was blinded to the treatment dose and time point of the photograph) and muscle strength.	Month 7
Secondary	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.	All of the participants who discontinued prior to month 4 evaluations were classed as non-responders. For participants missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value.; Analysis split by screening strata of mUFC Stratum 1: mUFC 1.5x to < 2.0 x ULN Stratum 2: mUFC 2.0x to <= 5.0 x ULN	Month 7
Secondary	Percentage of Patients That Attain a Reduction of at Least 50% in mUFC From Baseline	All of the participants who discontinued prior to month 4 evaluations were classed as non-responders. For participants missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value.; Analysis split by screening strata of mUFC; Stratum 1:	Months 7, 12, 24 & 36
Secondary	Percent of Participants Attaining a Time to First Achievement of at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points	Time to first achievement of a 5by randomized groups.0% reduction in mUFC from baseline	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)
Secondary	Percent of Participants With a Duration of at Least 50% Reduction in mUFC From Baseline at Indicated Time Points	Duration of 50% reduction from baseline is defined as the period starting from the date of patient's first 50% reduction from baseline	Months 6, 12 & 18
Secondary	Pharmacokinetic (PK) Parameter: Ctrough	Pasireotide trough levels (Ctrough) was 1 of the parameters used for PK assessments. Ctrough is the pre-dose PK concentration with an elapsed time from previous injection of 28+/-2 days. All patients randomized to the study had at least 1 PK observation & were therefore included in the pharmacokinetic analysis set. PK observations with missing concentrations, missing dose, missing elapsed time or an elapsed time from previous injection outside of 28 ±2 days window were excluded. Given that SOM230 LAR was administered once a month, Ctrough was collected every 28 days and thus this provides a summary of Ctrough values provided by incident dose (last dose administered prior to PK sample collection), not by randomized dose, hence each column is equivalent to an incident dose & not an arm/group. Patients randomized to either 10mg or 30mg could be titrated down to 5mg due to safety, or titrated up to 40mg, hence the 4 incident doses/columns that were allowed per protocol during this study.	Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337
Secondary	Pharmacokinetic (PK) Parameter: Cmax	Pasireotide peak levels (Cmax) was one of the parameters used for PK assessments. Cmax is the post-dose PK concentration with an elapsed time from the previous injection of 21+/-2 days. All patients randomized to the study had at least one PK observation and were therefore included in the pharmacokinetic analysis set (PAS). Cmax PK observations ("Day 20" and "Day 104") with an elapsed time from the previous injection outside of 21+/-2 days window were excluded. Given that SOM230 LAR was administered once a month, the Cmax were collected every 28 days in this study, thus this provides a summary of Cmax values provided by incident dose (last dose administered prior to PK sample collection), not by randomized dose, hence each column is equivalent to an incident dose and not an arm/group. Patients randomized to either the 10mg or 30mg could be titrated down to 5mg due to safety, or titrated up to 40mg, hence the 4 incident doses/columns that were allowed per protocol during this study.	Days 22, 106, 190
Secondary	Actual Change in Standardized Score of Cushing's Disease HRQoL (CushingQOL) Score From Baseline	CushingQol is a disease-specific patient-reported outcome instrument. It is a single-domain 12 item Cushing's disease quality of life instrument. The Cushing's syndrome quality of life (CushingQoL) questionnaire is a single domain questionnaire which includes 12 self-report items scored using a five point Likert scale anchored at (1=always/very much and 5=never/not at all). The patient is asked to report what they think or feel about their Cushing's syndrome and how much the illness has interfered in usual activities over the past 4 weeks. The total score is standardized on a 0-100 scale with lower scores indicating a greater impact on quality of life.	Months 7, 12, 24 & 36
Secondary	Actual Change in SF-12v2 Score From Baseline - Mental Component Summary	SF-12v2 General Health Survey is a general patient reported outcome instrument over time. It is scored to provide eight health domain scores (Bodily Pain (BP), General Health (GH), Physical Functioning (PF), Role-Physical (RP), Social Functioning (SF), Role-Emotional (RE), Vitality (VT) and Mental Health (MH)). These eight domain scores can be combined to form two summary scores reflecting overall physical and mental health: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The analyses reported here focus on PCS and MCS scores. The domain scores use a norm-based score, which standardizes the scores with respect to the mean and standard deviation of a nationally representative sample of United States (US) adults. These are the scores on the original scale which have not been transformed in any way. The possible range of scores is 0 to 100, with higher scores representing better outcomes.	Months 7, 12 & 24
Secondary	Actual Change in SF-12v2 Score From Baseline - Physical Component Summary	SF-12v2 General Health Survey is a general patient reported outcome instrument over time. It is scored to provide eight health domain scores (Bodily Pain (BP), General Health (GH), Physical Functioning (PF), Role-Physical (RP), Social Functioning (SF), Role-Emotional (RE), Vitality (VT) and Mental Health (MH)). These eight domain scores can be combined to form two summary scores reflecting overall physical and mental health: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The analyses reported here focus on PCS and MCS scores. The domain scores use a norm-based score, which standardizes the scores with respect to the mean and standard deviation of a nationally representative sample of United States (US) adults. These are the scores on the original scale which have not been transformed in any way. The possible range of scores is 0 to 100, with higher scores representing better outcomes.	Months 7, 12 & 24