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

A Randomized, Double-blind, Multicenter, Phase III Study to Evaluate the Efficacy and Safety of Pasireotide LAR in Patients With Cushing's Disease

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01374906

Enrollment

150

Registered

2011-06-16

Start date

2011-11-04

Completion date

2016-12-21

Last updated

2018-05-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

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

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.

Interventions

DRUGpasireotide 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).

DRUGSOM230 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.

DRUGSOM230 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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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

Design outcomes

Primary

Measure	Time frame	Description
Percentage Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 Regardless of Dose Titration	Month 7	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

Measure	Time frame	Description
Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline	baseline, Month 7 (M7), Month 12 (M12), Month 24 (M24) , Month 36 (M36)	Actual change in mUFC (nmol/24h) from baseline by randomized groups.
Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline	M7, M12, M24, M36	Percentage change in mUFC (nmol/24h) from baseline by randomized groups.
Percentage of Patients Who Attain mUFC ≤ 1.0 x ULN	M7, M12, M24, M36	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	M7, M12, M24, M36	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.	Month 7, 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	Month 7, Month12	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	Momth 7, Month 12	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	Month 6, 12, 18	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	Months 7, 12, 24 & 36	Percentage change in ACTH (pmol/L) from Baseline by randomized groups.
Percentage Change From Baseline on Serum Cortisol Over Time	Months 7, 12, 24 & 36	Percentage change in serum cortisol (nmol/L) from Baseline by randomized groups.
Actual Change From Baseline in Clinical Signs Over Time: Blood Pressure	Month 7	Change in blood pressure measurements from Baseline
Actual Change From Baseline in Clinical Signs Over Time: Body Mass Index (BMI)	Month 7	Change in BMI measurements from Baseline
Actual Change From Baseline in Clinical Signs Over Time: Weight	Month 7	Change in weight measurements from Baseline
Percentage of Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 and Had Not Had a Dose Increase at Month 4	Month 7	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 From Baseline in Clinical Signs Over Time: Waist Circumference	Month 7	Change in waist circumference measurements from Baseline
Actual Change From Baseline in Clinical Signs Over Time: Cholesterol & Triglycerides	Month 7	Change in parameter measurements: cholesterol & triglycerides from Baseline
Percentage Change From Baseline in Clinical Signs Over Time	Month 7	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	Month 7	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.	Month 7	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	Months 7, 12, 24 & 36	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	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)	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	Months 6, 12 & 18	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	Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337	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	Days 22, 106, 190	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	Months 7, 12, 24 & 36	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	Months 7, 12 & 24	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	Months 7, 12 & 24	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 From Baseline in Clinical Signs Over Time: Body Composition: Region	Month 7	Change in body composition: region measurements from Baseline

Countries

Argentina, Belgium, Brazil, Canada, China, France, Germany, India, Israel, Italy, Japan, Netherlands, Peru, Poland, Russia, Spain, Thailand, Turkey (Türkiye), United Kingdom, United States

Participant flow

Recruitment details

At least 148 patients (Pts.) were planned & 150 were randomized & analyzed. Pts. were all treated with either pasireotide long-acting 10 mg or pasireotide long-acting 30 mg. 81 Pts. completed the Core phase & entered the Extension phase with 39 completing the Extension phase.

Participants by arm

Arm	Count
10 mg Pasireotide LAR Dose Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	74
30 mg Pasireotide LAR Dose Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.	76
Total	150

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Abnormal laboratory value(s)	0	3
Overall Study	Administrative problems	2	2
Overall Study	Adverse Event	10	11
Overall Study	Death	0	2
Overall Study	Protocol Violation	2	2
Overall Study	Unsatisfactory therapeutic effect	11	19
Overall Study	Withdrawal by Subject	15	9

Baseline characteristics

Characteristic	30 mg Pasireotide LAR Dose	10 mg Pasireotide LAR Dose	Total
Age, Continuous	38.6 years STANDARD_DEVIATION 12.99	38.3 years STANDARD_DEVIATION 12.52	38.5 years STANDARD_DEVIATION 12.72
Race/Ethnicity, Customized Asian	24 Participants	27 Participants	51 Participants
Race/Ethnicity, Customized Black	0 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Caucasian	44 Participants	39 Participants	83 Participants
Race/Ethnicity, Customized Other	8 Participants	6 Participants	14 Participants
Sex: Female, Male Female	60 Participants	58 Participants	118 Participants
Sex: Female, Male Male	16 Participants	16 Participants	32 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	73 / 74	76 / 76	149 / 150
serious Total, serious adverse events	22 / 74	19 / 76	41 / 150

Outcome results

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.

Time frame: Month 7