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

Primary Purpose

Cushing's Disease

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
pasireotide LAR
SOM230 LAR 30 mg
SOM230 LAR 10 mg
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cushing's Disease focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • ClinTriCo
  • University of California at Los Angeles UCLA Tiverton
  • Harbor-UCLA Medical Center LA Biomed
  • Emory University School of Medicine/Winship Cancer Institute G2304 - C2301
  • Pituitary Center, Division of Endocrinology SC
  • University of Michigan Comprehensive Cancer Center SC-2
  • Mount Sinai School of Medicine Mt. Sinai Medical Center
  • Oregon Health & Sciences University DeptofOregonHealth&Sciences(2)
  • University of Pennsylvania - Clinical Studies Unit Unniv SC
  • Vanderbilt University Medical Center CSOM230G2304
  • Swedish Medical Center Swedish
  • Medical College of Wisconsin MCW 2
  • Novartis Investigative Site
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Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

10 mg LAR dose

30 mg LAR dose

Arm Description

Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms.

Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline
Actual change in mUFC (nmol/24h) from baseline by randomized groups.
Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline
Percentage change in mUFC (nmol/24h) from baseline by randomized groups.
Percentage of Patients Who Attain mUFC ≤ 1.0 x ULN
Controlled responder: mUFC ≤ 1.0×ULN by randomized groups.
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.
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.
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.
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.
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.
Percentage Change From Baseline on Plasma Adrenocorticotropic Hormone (ACTH) Over Time
Percentage change in ACTH (pmol/L) from Baseline by randomized groups.
Percentage Change From Baseline on Serum Cortisol Over Time
Percentage change in serum cortisol (nmol/L) from Baseline by randomized groups.
Actual Change From Baseline in Clinical Signs Over Time: Blood Pressure
Change in blood pressure measurements from Baseline
Actual Change From Baseline in Clinical Signs Over Time: Body Mass Index (BMI)
Change in BMI measurements from Baseline
Actual Change From Baseline in Clinical Signs Over Time: Weight
Change in weight measurements from Baseline
Actual Change From Baseline in Clinical Signs Over Time: Body Composition: Region
Change in body composition: region measurements from Baseline
Actual Change From Baseline in Clinical Signs Over Time: Waist Circumference
Change in waist circumference measurements from Baseline
Actual Change From Baseline in Clinical Signs Over Time: Cholesterol & Triglycerides
Change in parameter measurements: cholesterol & triglycerides from Baseline
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
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.
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
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:
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
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
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.
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.
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.
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.
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.

Full Information

First Posted
June 14, 2011
Last Updated
April 25, 2018
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01374906
Brief Title
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

2. Study Status

Record Verification Date
April 2018
Overall Recruitment Status
Completed
Study Start Date
November 4, 2011 (Actual)
Primary Completion Date
December 21, 2016 (Actual)
Study Completion Date
December 21, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
150 (Actual)

8. Arms, Groups, and Interventions

Arm Title
10 mg LAR dose
Arm Type
Experimental
Arm Description
Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms.
Arm Title
30 mg LAR dose
Arm Type
Experimental
Arm Description
Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms.
Intervention Type
Drug
Intervention Name(s)
pasireotide LAR
Other Intervention Name(s)
SOM230
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
SOM230 LAR 30 mg
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
SOM230 LAR 10 mg
Intervention Description
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.
Primary Outcome Measure Information:
Title
Percentage Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 Regardless of Dose Titration
Description
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.
Time Frame
Month 7
Secondary Outcome Measure Information:
Title
Percentage of Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 and Had Not Had a Dose Increase at Month 4
Description
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.
Time Frame
Month 7
Title
Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline
Description
Actual change in mUFC (nmol/24h) from baseline by randomized groups.
Time Frame
baseline, Month 7 (M7), Month 12 (M12), Month 24 (M24) , Month 36 (M36)
Title
Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline
Description
Percentage change in mUFC (nmol/24h) from baseline by randomized groups.
Time Frame
M7, M12, M24, M36
Title
Percentage of Patients Who Attain mUFC ≤ 1.0 x ULN
Description
Controlled responder: mUFC ≤ 1.0×ULN by randomized groups.
Time Frame
M7, M12, M24, M36
Title
Percentage of Patients Who Attain mUFC ≤1.0 x ULN or Have at Least 50 % Reduction From Baseline in mUFC
Description
Controlled responder: mUFC ≤ 1.0×ULN. Partially controlled responder: at least 50% reduction in mUFC from Baseline, and mUFC >1.0×ULN.
Time Frame
M7, M12, M24, M36
Title
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.
Description
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.
Time Frame
Month 7, Month 12
Title
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
Description
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.
Time Frame
Month 7, Month12
Title
Percent of Participants Attaining a mUFC ≤ 1.0 x ULN or at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points
Description
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.
Time Frame
Momth 7, Month 12
Title
Percent of Participants Attaining a Duration of Controlled or Partially Controlled Response at Indicated Time Points
Description
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.
Time Frame
Month 6, 12, 18
Title
Percentage Change From Baseline on Plasma Adrenocorticotropic Hormone (ACTH) Over Time
Description
Percentage change in ACTH (pmol/L) from Baseline by randomized groups.
Time Frame
Months 7, 12, 24 & 36
Title
Percentage Change From Baseline on Serum Cortisol Over Time
Description
Percentage change in serum cortisol (nmol/L) from Baseline by randomized groups.
Time Frame
Months 7, 12, 24 & 36
Title
Actual Change From Baseline in Clinical Signs Over Time: Blood Pressure
Description
Change in blood pressure measurements from Baseline
Time Frame
Month 7
Title
Actual Change From Baseline in Clinical Signs Over Time: Body Mass Index (BMI)
Description
Change in BMI measurements from Baseline
Time Frame
Month 7
Title
Actual Change From Baseline in Clinical Signs Over Time: Weight
Description
Change in weight measurements from Baseline
Time Frame
Month 7
Title
Actual Change From Baseline in Clinical Signs Over Time: Body Composition: Region
Description
Change in body composition: region measurements from Baseline
Time Frame
Month 7
Title
Actual Change From Baseline in Clinical Signs Over Time: Waist Circumference
Description
Change in waist circumference measurements from Baseline
Time Frame
Month 7
Title
Actual Change From Baseline in Clinical Signs Over Time: Cholesterol & Triglycerides
Description
Change in parameter measurements: cholesterol & triglycerides from Baseline
Time Frame
Month 7
Title
Percentage Change From Baseline in Clinical Signs Over Time
Description
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
Time Frame
Month 7
Title
Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs
Description
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.
Time Frame
Month 7
Title
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.
Description
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
Time Frame
Month 7
Title
Percentage of Patients That Attain a Reduction of at Least 50% in mUFC From Baseline
Description
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:
Time Frame
Months 7, 12, 24 & 36
Title
Percent of Participants Attaining a Time to First Achievement of at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points
Description
Time to first achievement of a 5by randomized groups.0% reduction in mUFC from baseline
Time Frame
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)
Title
Percent of Participants With a Duration of at Least 50% Reduction in mUFC From Baseline at Indicated Time Points
Description
Duration of 50% reduction from baseline is defined as the period starting from the date of patient's first 50% reduction from baseline
Time Frame
Months 6, 12 & 18
Title
Pharmacokinetic (PK) Parameter: Ctrough
Description
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.
Time Frame
Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337
Title
Pharmacokinetic (PK) Parameter: Cmax
Description
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.
Time Frame
Days 22, 106, 190
Title
Actual Change in Standardized Score of Cushing's Disease HRQoL (CushingQOL) Score From Baseline
Description
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.
Time Frame
Months 7, 12, 24 & 36
Title
Actual Change in SF-12v2 Score From Baseline - Mental Component Summary
Description
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.
Time Frame
Months 7, 12 & 24
Title
Actual Change in SF-12v2 Score From Baseline - Physical Component Summary
Description
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.
Time Frame
Months 7, 12 & 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
ClinTriCo
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85381
Country
United States
Facility Name
University of California at Los Angeles UCLA Tiverton
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Harbor-UCLA Medical Center LA Biomed
City
Torrance
State/Province
California
ZIP/Postal Code
90509
Country
United States
Facility Name
Emory University School of Medicine/Winship Cancer Institute G2304 - C2301
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Pituitary Center, Division of Endocrinology SC
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
University of Michigan Comprehensive Cancer Center SC-2
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-0944
Country
United States
Facility Name
Mount Sinai School of Medicine Mt. Sinai Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Oregon Health & Sciences University DeptofOregonHealth&Sciences(2)
City
Portland
State/Province
Oregon
ZIP/Postal Code
97201
Country
United States
Facility Name
University of Pennsylvania - Clinical Studies Unit Unniv SC
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Vanderbilt University Medical Center CSOM230G2304
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37212-3139
Country
United States
Facility Name
Swedish Medical Center Swedish
City
Seattle
State/Province
Washington
ZIP/Postal Code
98122-4379
Country
United States
Facility Name
Medical College of Wisconsin MCW 2
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Facility Name
Novartis Investigative Site
City
Buenos Aires
ZIP/Postal Code
C1232AAC
Country
Argentina
Facility Name
Novartis Investigative Site
City
Cordoba
ZIP/Postal Code
X5009BSN
Country
Argentina
Facility Name
Novartis Investigative Site
City
Edegem
State/Province
Antwerpen
ZIP/Postal Code
2650
Country
Belgium
Facility Name
Novartis Investigative Site
City
Jette
State/Province
Brussel
ZIP/Postal Code
1090
Country
Belgium
Facility Name
Novartis Investigative Site
City
Bruxelles
ZIP/Postal Code
1070
Country
Belgium
Facility Name
Novartis Investigative Site
City
Gent
ZIP/Postal Code
9000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Fortaleza
State/Province
CE
ZIP/Postal Code
60020-181
Country
Brazil
Facility Name
Novartis Investigative Site
City
Rio de Janeiro
State/Province
RJ
ZIP/Postal Code
21941-913
Country
Brazil
Facility Name
Novartis Investigative Site
City
Ribeirao Preto
State/Province
SP
ZIP/Postal Code
14048-900
Country
Brazil
Facility Name
Novartis Investigative Site
City
São Paulo
State/Province
SP
ZIP/Postal Code
05403 000
Country
Brazil
Facility Name
Novartis Investigative Site
City
Halifax
State/Province
Nova Scotia
ZIP/Postal Code
B3H 1V7
Country
Canada
Facility Name
Novartis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2L 4M1
Country
Canada
Facility Name
Novartis Investigative Site
City
Sherbrooke
State/Province
Quebec
ZIP/Postal Code
J1N 5N4
Country
Canada
Facility Name
Novartis Investigative Site
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100730
Country
China
Facility Name
Novartis Investigative Site
City
Chengdu
State/Province
Sichuan
ZIP/Postal Code
610041
Country
China
Facility Name
Novartis Investigative Site
City
Shanghai
ZIP/Postal Code
200025
Country
China
Facility Name
Novartis Investigative Site
City
Shanghai
ZIP/Postal Code
200040
Country
China
Facility Name
Novartis Investigative Site
City
Besancon cedex
ZIP/Postal Code
25030
Country
France
Facility Name
Novartis Investigative Site
City
Caen Cedex9
ZIP/Postal Code
14033
Country
France
Facility Name
Novartis Investigative Site
City
Le Kremlin Bicetre
ZIP/Postal Code
94275
Country
France
Facility Name
Novartis Investigative Site
City
Lille Cedex
ZIP/Postal Code
59037
Country
France
Facility Name
Novartis Investigative Site
City
Marseille Cédex 5
ZIP/Postal Code
13385
Country
France
Facility Name
Novartis Investigative Site
City
Pessac Cedex
ZIP/Postal Code
33604
Country
France
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Facility Name
Novartis Investigative Site
City
Erlangen
ZIP/Postal Code
91054
Country
Germany
Facility Name
Novartis Investigative Site
City
Germering
ZIP/Postal Code
82110
Country
Germany
Facility Name
Novartis Investigative Site
City
Wurzburg
ZIP/Postal Code
97080
Country
Germany
Facility Name
Novartis Investigative Site
City
Mumbai
State/Province
Maharashtra
ZIP/Postal Code
400012
Country
India
Facility Name
Novartis Investigative Site
City
Vellore
State/Province
Tamil Nadu
ZIP/Postal Code
632004
Country
India
Facility Name
Novartis Investigative Site
City
New Delhi
ZIP/Postal Code
110 029
Country
India
Facility Name
Novartis Investigative Site
City
Petach Tikva
ZIP/Postal Code
49100
Country
Israel
Facility Name
Novartis Investigative Site
City
Ancona
State/Province
AN
ZIP/Postal Code
60126
Country
Italy
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20149
Country
Italy
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20162
Country
Italy
Facility Name
Novartis Investigative Site
City
Padova
State/Province
PD
ZIP/Postal Code
35128
Country
Italy
Facility Name
Novartis Investigative Site
City
Napoli
ZIP/Postal Code
80131
Country
Italy
Facility Name
Novartis Investigative Site
City
Nagoya
State/Province
Aichi
ZIP/Postal Code
460-0001
Country
Japan
Facility Name
Novartis Investigative Site
City
Fukuoka city
State/Province
Fukuoka
ZIP/Postal Code
812-8582
Country
Japan
Facility Name
Novartis Investigative Site
City
Maebashi city
State/Province
Gunma
ZIP/Postal Code
371 8511
Country
Japan
Facility Name
Novartis Investigative Site
City
Sapporo-city
State/Province
Hokkaido
ZIP/Postal Code
060-8648
Country
Japan
Facility Name
Novartis Investigative Site
City
Kobe-city
State/Province
Hyogo
ZIP/Postal Code
650-0017
Country
Japan
Facility Name
Novartis Investigative Site
City
Nankoku-city
State/Province
Kochi
ZIP/Postal Code
783-8505
Country
Japan
Facility Name
Novartis Investigative Site
City
Kyoto-city
State/Province
Kyoto
ZIP/Postal Code
612-8555
Country
Japan
Facility Name
Novartis Investigative Site
City
Suita-city
State/Province
Osaka
ZIP/Postal Code
565-0871
Country
Japan
Facility Name
Novartis Investigative Site
City
Bunkyo-ku
State/Province
Tokyo
ZIP/Postal Code
113-8603
Country
Japan
Facility Name
Novartis Investigative Site
City
Minato-ku
State/Province
Tokyo
ZIP/Postal Code
105-8470
Country
Japan
Facility Name
Novartis Investigative Site
City
Shinjuku-ku
State/Province
Tokyo
ZIP/Postal Code
162-8666
Country
Japan
Facility Name
Novartis Investigative Site
City
Osaka
ZIP/Postal Code
534-0021
Country
Japan
Facility Name
Novartis Investigative Site
City
Rotterdam
ZIP/Postal Code
3015 CE
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Jesus Maria
State/Province
Lima
ZIP/Postal Code
11
Country
Peru
Facility Name
Novartis Investigative Site
City
Miraflores
State/Province
Lima
ZIP/Postal Code
18
Country
Peru
Facility Name
Novartis Investigative Site
City
Gdansk
ZIP/Postal Code
80-952
Country
Poland
Facility Name
Novartis Investigative Site
City
Poznan
ZIP/Postal Code
60-355
Country
Poland
Facility Name
Novartis Investigative Site
City
Warszawa
ZIP/Postal Code
00-909
Country
Poland
Facility Name
Novartis Investigative Site
City
Wroclaw
ZIP/Postal Code
50-367
Country
Poland
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
119296
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
St.- Petersburg
ZIP/Postal Code
199034
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Sevilla
State/Province
Andalucia
ZIP/Postal Code
41013
Country
Spain
Facility Name
Novartis Investigative Site
City
Alzira
State/Province
Comunidad Valenciana
ZIP/Postal Code
46600
Country
Spain
Facility Name
Novartis Investigative Site
City
Barcelona
ZIP/Postal Code
08041
Country
Spain
Facility Name
Novartis Investigative Site
City
Bangkok
ZIP/Postal Code
10330
Country
Thailand
Facility Name
Novartis Investigative Site
City
Bangkok
ZIP/Postal Code
10700
Country
Thailand
Facility Name
Novartis Investigative Site
City
Diskapi / Ankara
State/Province
Ankara
ZIP/Postal Code
06110
Country
Turkey
Facility Name
Novartis Investigative Site
City
Istanbul
State/Province
TUR
ZIP/Postal Code
34098
Country
Turkey
Facility Name
Novartis Investigative Site
City
Izmir
ZIP/Postal Code
35340
Country
Turkey
Facility Name
Novartis Investigative Site
City
Salford
State/Province
Manchester
ZIP/Postal Code
M6 8HD
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Norwich
ZIP/Postal Code
NR4 7UY
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Sheffield
ZIP/Postal Code
S5 7AU
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Southampton
ZIP/Postal Code
SO16 6YD
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Citations:
PubMed Identifier
32385851
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.
Results Reference
derived
PubMed Identifier
31804965
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.
Results Reference
derived
PubMed Identifier
31465533
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.
Results Reference
derived
PubMed Identifier
29032078
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. Erratum In: Lancet Diabetes Endocrinol. 2018 Jan;6(1):e1.
Results Reference
derived
PubMed Identifier
27405306
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.
Results Reference
derived

Learn more about this trial

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

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