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The main purpose of this prospective, multicenter, open-label phase II study, was to evaluate the efficacy and safety of pasireotide alone or in combination with cabergoline in patients with Cushing's disease.
This was an open-label, multi-center, international, non-comparative study with adult patients with confirmed diagnosis of Cushing's disease. Given the fact that CD patients may need a multimodality treatment approach, the trial design aimed to mimic CD treatment by using a medical stepwise approach. Therefore, the whole patient population started treatment with Pasireotide and only in patients within this population who did not achieve biochemical control, cabergoline was added.
The whole patient population had never received pasireotide or had received it in the past (reasons of discontinuation not related to safety).
Core Phase
Extension Phase
• After 35 weeks of treatment in core phase, patients had the option to continue study treatment if pasireotide was not yet approved for commercial use and/or reimbursed - if country reimbursement was applicable - in each respective country, or until 31st December 2017, or once an applicable roll over protocol became available, or whichever occurred first.
Novartis had a local transition plan in order to ensure that all trial patients had access to the study medication without any delay in their treatment
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| pasireotide +/- cabergoline | Experimental | pasireotide alone or with cabergoline |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pasireotide with or without cabergoline | Drug | The trial consisted of Pasireotide-untreated patients who started pasireotide 0.6mg twice a day for 8 weeks. If biochemical control was not achieved by the end of the 8 weeks, and the 0.6mg dose is well-tolerated, the dose was increased to 0.9mg twice a day for another 8 weeks. If biochemical control is not achieved, cabergoline was added and patients began combination treatment with cabergoline at the starting dose of 0.5mg once a day for 8 weeks. If biochemical control is still not achieved at the end of the third 8 week period, the dose of cabergoline was increased to 1.0mg once a day. Patients could also immediately start the combination treatment by adding cabergoline 0.5mg once a day at study entry to their current maximal tolerated dose of pasireotide. Patients continued with the combination treatment for 8 weeks. If biochemical control was not not achieved by the end of the 8 week period, the dose of cabergoline was increased to 1mg once a day. |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN Collected or Imputed at Week 35 | Participants who attained mUFC ≤ 1.0 x ULN (upper limit of normal) with pasireotide alone or in combination with cabergoline. The 24h-UFC concentration results from three samples, collected during the screening period, were averaged to obtain the Baseline urinary free cortisol level. mean 24h-UFC was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit. Imputation: subjects who completed the end of treatment visit at Week 35, but had missing evaluation of mean urinary free cortisol (mUFC). The last available mUFC assessment at or after previous visit (week) before last week was carried forward as the last week mUFC assessment. | Baseline up to week 35 |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured. | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension |
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Inclusion criteria:
Written informed consent obtained prior to screening procedures
Adult patients with confirmed diagnosis of ACTH-dependent Cushing's disease as evidenced by all of the following:
Patients with de novo Cushing's disease could only be included only if they were not considered candidates for pituitary surgery (e.g. poor surgical candidates, surgically unapproachable tumors, patients who refused to have surgical treatment)
Male or female patients aged 18 years or greater
Karnofsky performance status ≥ 60 (i.e. required occasional assistance, but was able to care for most of their personal needs)
Patients on medical treatment for Cushing's disease the following washout periods must have been completed before screening assessments were performed
Patients could have been considered to enter the trial if they met any one of the following criteria: 1) They were naive to pasireotide 2) They had received pasireotide in the past and have been discontinued because of lack of efficacy (2 weeks for washout prior to screening for patients treated with pasireotide subcutaneously and 12 weeks of washout prior to screening for patients treated with pasireotide LAR) 3) Patients who were on maximal tolerated dose but had not achieved biochemical control
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, if they were using highly effective methods of contraception during dosing and for 30 days after stopping study medication.
Male participants in the trial must have agreed to use a condom during intercourse, and not to father a child during the study and for the period of 30 days following stopping of the study treatment.
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham The Kirklin Clinic | Birmingham | Alabama | 35294 | United States | ||
| Oregon Health and Science University SOM230B2411 |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37876540 | Derived | Feelders RA, Fleseriu M, Kadioglu P, Bex M, Gonzalez-Devia D, Boguszewski CL, Yavuz DG, Patino H, Pedroncelli AM, Maamari R, Chattopadhyay A, Biller BMK, Pivonello R. Long-term efficacy and safety of subcutaneous pasireotide alone or in combination with cabergoline in Cushing's disease. Front Endocrinol (Lausanne). 2023 Oct 9;14:1165681. doi: 10.3389/fendo.2023.1165681. eCollection 2023. |
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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
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| ID | Title | Description |
|---|---|---|
| FG000 | All Patients | Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Core Phase |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 27, 2019 | Aug 28, 2020 |
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|
| Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN |
Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured. |
| Baseline up to week 235 |
| Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured. | Baseline up to week 235 |
| Duration (Weeks) of Controlled or Partially Controlled Response | 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% from the first time | from the date patient's first normalization (mUFC ≤ 1.0xULN) or at least 50% reduction from baseline up to the date when the patient's mUFC > 1.0 x ULN |
| Plasma Adrenocorticotropic Hormone (ACTH) | A pre-dose blood draw for plasma ACTH sampling was taken at visits. Samples were analyzed by a central laboratory. | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension |
| Serum Cortisol Levels | A pre-dose blood draw for an 8 am fasting serum cortisol measurement were taken at visits. Samples were analyzed by a central laboratory. | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension |
| Sitting Systolic Blood Pressure at Week 35 | The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures | Baseline and week 35 |
| Sitting Diastolic Blood Pressure at Week 35 | The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures | Baseline and week 35 |
| Body Weight at Week 35 | Weight was was one of the measures of clinical symptoms of CD | Baseline and week 35 |
| Body Mass Index at Week 35 | Body mass index was one of the measurements of clinical symptoms of CD. Body mass index=weight in kg divided by the square of the body height (in meters) | Baseline and week 35 |
| Waist Circumference at Week 35 | Waist circumference was one of the measurements of clinical signs of CD | Baseline and week 35 |
| LDL, HDL and Total Cholesterol at Week 35 | LDL=Low density lipoprotein, HDL=high density llipoprotein and total protein were analyzed by a central laboratory | Baseline and week 35 |
| Mean Scores of Cushing QoL Standardized Score at Week 17 and 35 | Patients who completed nine or more items for the 12-item Cushing's syndrome QoL questionaire were considered evaluable for that assessment. Raw scores were obtained for the 12 items using the following scoring: 1) always or very much, 2) often or quite a bit, 3) sometimes or somewhat, 4) rarely or very little, 5) never or not at all. Then the standardized score, Y, was calculated for each patient as follows: Y = 100* (X - n) / n*5 - n*1) = 100 * (X - n) / 4*n where X denoted the raw score and n the number of questions answered by the patient. The higher the score, the better the QoL. The best possible standardized score was 100 and the worst possible standardized score was 0 | Baseline and week 17 and 35 |
| Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | 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. | Baseline, week 17 and 35 |
| Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension |
| Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension |
| Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension |
| Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension |
| Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension |
| Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad were assessed. Two photographs, one frontal and one lateral from the shoulders up will be taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position will be taken to assess striae, and hirsutism. The photographs must be assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Baseline, weeks 1, 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension |
| Number of Patients With Shift From Standing Easily to Not Being Able to Stand | To test proximal muscle strength patients should be placed in a low seated position (for instance on an examination room stool). They should be asked to extend the arms in front of them. From this seated position patients will be asked to stand up. Patients will be evaluated using the following scale: 3. - completely unable to stand 2. - able to stand only by using arms as assistance 1. - able to stand after several efforts without using arms as assistance 0. - able to stand easily with arms extended | Baseline up to week 267 |
| Portland |
| Oregon |
| 97239 |
| United States |
| Novartis Investigative Site | Caba | Buenos Aires | C1280AEB | Argentina |
| Novartis Investigative Site | Ghent | 9000 | Belgium |
| Novartis Investigative Site | Leuven | 3000 | Belgium |
| Novartis Investigative Site | Curitiba | Paraná | 80030-110 | Brazil |
| Novartis Investigative Site | Rio de Janeiro | Rio de Janeiro | 21941-913 | Brazil |
| Novartis Investigative Site | Porto Alegre | Rio Grande do Sul | 90560-030 | Brazil |
| Novartis Investigative Site | São Paulo | São Paulo | 05403 000 | Brazil |
| Novartis Investigative Site | Bogota | Cundinamarca | 110111 | Colombia |
| Novartis Investigative Site | Vandœuvre-lès-Nancy | 54511 | France |
| Novartis Investigative Site | Erlangen | 91054 | Germany |
| Novartis Investigative Site | Athens | 106 76 | Greece |
| Novartis Investigative Site | Thessaloniki | GR 54636 | Greece |
| Novartis Investigative Site | Budapest | 1062 | Hungary |
| Novartis Investigative Site | Budapest | 1085 | Hungary |
| Novartis Investigative Site | Vellore | Tamil Nadu | 632004 | India |
| Novartis Investigative Site | Chandigarh | 160 012 | India |
| Novartis Investigative Site | New Delhi | 110029 | India |
| Novartis Investigative Site | Naples | 80131 | Italy |
| Novartis Investigative Site | Wilayah Persekutuan | 62502 | Malaysia |
| Novartis Investigative Site | Mexico City | Mexico City | 14269 | Mexico |
| Novartis Investigative Site | Durango | 34270 | Mexico |
| Novartis Investigative Site | Rotterdam | 3015 GD | Netherlands |
| Novartis Investigative Site | Málaga | Andalusia | 29010 | Spain |
| Novartis Investigative Site | Alzira | Valencia | 46600 | Spain |
| Novartis Investigative Site | Pendik / Istanbul | Turkey | 34899 | Turkey (Türkiye) |
| Novartis Investigative Site | Istanbul | TUR | 34098 | Turkey (Türkiye) |
| Novartis Investigative Site | Izmir | 35340 | Turkey (Türkiye) |
| COMPLETED |
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| NOT COMPLETED |
|
|
| Extension Phase |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Patients | Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Number | participants |
| |||||||||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Number | Participants |
| |||||||||||||||||||||||
| Cushing's disease status | De novo = newly diagnosed and persistent/recurrent = xxxxxxxx | Number | Participants |
| ||||||||||||||||||||||
| Clinical symptoms of facial rubor | Clinical symptoms of CD for facial rubor by severity | Number | Participants |
| ||||||||||||||||||||||
| Clinical symptoms of hirsutism | Clinical symptoms of CD for hirsutism by severity | Number | Participants |
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| Clinical symptoms of striae | Clinical symptoms of CD for striae by severity | Number | Participants |
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| Clinical symptoms of supraclavicular fat pad | Clinical symptoms of CD for supraclavicular fat pad by severity | Number | Participants |
| ||||||||||||||||||||||
| Clinical symptoms of dorsal fat pad | Clinical symptoms of CD for dorsal fat pad severity | Number | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN Collected or Imputed at Week 35 | Participants who attained mUFC ≤ 1.0 x ULN (upper limit of normal) with pasireotide alone or in combination with cabergoline. The 24h-UFC concentration results from three samples, collected during the screening period, were averaged to obtain the Baseline urinary free cortisol level. mean 24h-UFC was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit. Imputation: subjects who completed the end of treatment visit at Week 35, but had missing evaluation of mean urinary free cortisol (mUFC). The last available mUFC assessment at or after previous visit (week) before last week was carried forward as the last week mUFC assessment. | Full analysis set | Posted | Number | 95% Confidence Interval | percentage of responders | Baseline up to week 35 |
|
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| Secondary | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured. | Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored | Posted | Mean | Standard Deviation | nmol/24h | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension |
|
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| Secondary | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured. | Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored | Posted | Number | 95% Confidence Interval | percentage of responders | Baseline up to week 235 |
|
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| Secondary | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured. | Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored | Posted | Number | 95% Confidence Interval | percentage of responders | Baseline up to week 235 |
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| Secondary | Duration (Weeks) of Controlled or Partially Controlled Response | 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% from the first time | Core and extension full analysis set | Posted | Median | 95% Confidence Interval | weeks | from the date patient's first normalization (mUFC ≤ 1.0xULN) or at least 50% reduction from baseline up to the date when the patient's mUFC > 1.0 x ULN |
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| Secondary | Plasma Adrenocorticotropic Hormone (ACTH) | A pre-dose blood draw for plasma ACTH sampling was taken at visits. Samples were analyzed by a central laboratory. | Full analysis set | Posted | Mean | Standard Deviation | pmol/L | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension |
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| Secondary | Serum Cortisol Levels | A pre-dose blood draw for an 8 am fasting serum cortisol measurement were taken at visits. Samples were analyzed by a central laboratory. | Full analysis set | Posted | Mean | Standard Deviation | nmol/L | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension |
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| Secondary | Sitting Systolic Blood Pressure at Week 35 | The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures | Full analysis set | Posted | Mean | Standard Deviation | mmHg | Baseline and week 35 |
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| Secondary | Sitting Diastolic Blood Pressure at Week 35 | The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures | Full analysis set | Posted | Mean | Standard Deviation | mmHg | Baseline and week 35 |
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| Secondary | Body Weight at Week 35 | Weight was was one of the measures of clinical symptoms of CD | Full analysis set | Posted | Mean | Standard Deviation | kg | Baseline and week 35 |
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| Secondary | Body Mass Index at Week 35 | Body mass index was one of the measurements of clinical symptoms of CD. Body mass index=weight in kg divided by the square of the body height (in meters) | Full analysis set | Posted | Mean | Standard Deviation | kg/m2 | Baseline and week 35 |
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| Secondary | Waist Circumference at Week 35 | Waist circumference was one of the measurements of clinical signs of CD | Full analysis set | Posted | Mean | Standard Deviation | cm | Baseline and week 35 |
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| Secondary | LDL, HDL and Total Cholesterol at Week 35 | LDL=Low density lipoprotein, HDL=high density llipoprotein and total protein were analyzed by a central laboratory | Full analysis set | Posted | Mean | Standard Deviation | mmol/L | Baseline and week 35 |
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| Secondary | Mean Scores of Cushing QoL Standardized Score at Week 17 and 35 | Patients who completed nine or more items for the 12-item Cushing's syndrome QoL questionaire were considered evaluable for that assessment. Raw scores were obtained for the 12 items using the following scoring: 1) always or very much, 2) often or quite a bit, 3) sometimes or somewhat, 4) rarely or very little, 5) never or not at all. Then the standardized score, Y, was calculated for each patient as follows: Y = 100* (X - n) / n*5 - n*1) = 100 * (X - n) / 4*n where X denoted the raw score and n the number of questions answered by the patient. The higher the score, the better the QoL. The best possible standardized score was 100 and the worst possible standardized score was 0 | Full analysis set | Posted | Mean | Standard Deviation | scores on a scale | Baseline and week 17 and 35 |
|
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| Secondary | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | 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 analysis set | Posted | Mean | Standard Deviation | scores on a scale | Baseline, week 17 and 35 |
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| Secondary | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored | Posted | Number | participants | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension |
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| Secondary | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored | Posted | Number | participants | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension |
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| Secondary | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored | Posted | Number | participants | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension |
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| Secondary | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored | Posted | Number | participants | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension |
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| Secondary | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored | Posted | Number | participants | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension |
|
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| Secondary | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad were assessed. Two photographs, one frontal and one lateral from the shoulders up will be taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position will be taken to assess striae, and hirsutism. The photographs must be assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline | Full analysis set | Posted | Number | participants | Baseline, weeks 1, 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension |
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| Secondary | Number of Patients With Shift From Standing Easily to Not Being Able to Stand | To test proximal muscle strength patients should be placed in a low seated position (for instance on an examination room stool). They should be asked to extend the arms in front of them. From this seated position patients will be asked to stand up. Patients will be evaluated using the following scale: 3. - completely unable to stand 2. - able to stand only by using arms as assistance 1. - able to stand after several efforts without using arms as assistance 0. - able to stand easily with arms extended | Full analysis set | Posted | Number | participants | Baseline up to week 267 |
|
|
Adverse events were collected from first dose of study treatment until end of study treatment plus 28 days post treatment, up to maximum duration of 272 weeks
Any sign or symptom that occurs during the study treatment plus 28 days post treatment
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | All Patients | Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension | 3 | 68 | 15 | 68 | 67 | 68 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Coronary artery disease | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Glucocorticoid deficiency | Endocrine disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Intra-abdominal haematoma | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Death | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Multiple organ dysfunction syndrome | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Bile duct stone | Hepatobiliary disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Cholecystitis | Hepatobiliary disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Cholelithiasis | Hepatobiliary disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Abscess limb | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Cellulitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Varicella | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Hip fracture | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Muscle rupture | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Radius fracture | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Wound | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Aspartate aminotransferase increased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Gamma-glutamyltransferase increased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Intervertebral disc protrusion | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Bladder neoplasm | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (20.1) | Systematic Assessment |
| |
| Pituitary tumour benign | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (20.1) | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Presyncope | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Syncope | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Renal failure | Renal and urinary disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypertension | Vascular disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Shock haemorrhagic | Vascular disorders | MedDRA (20.1) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Bradycardia | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Mitral valve incompetence | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Flatulence | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Asthenia | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Cholelithiasis | Hepatobiliary disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hepatic steatosis | Hepatobiliary disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Gamma-glutamyltransferase increased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Glucose tolerance impaired | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypercholesterolaemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hyperuricaemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Vitamin B12 deficiency | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Vitamin D deficiency | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Somnolence | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Tremor | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Depression | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypertension | Vascular disorders | MedDRA (20.1) | Systematic Assessment |
|
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | 862-778-8300 | Novartis.email@novartis.com |
| SAP_000.pdf |
| Prot | Yes | No | No | Study Protocol | Jul 12, 2017 | Aug 28, 2020 | Prot_001.pdf |
| ID | Term |
|---|---|
| D000308 | Adrenocortical Hyperfunction |
| D010911 | Pituitary Neoplasms |
| D047748 | Pituitary ACTH Hypersecretion |
| ID | Term |
|---|---|
| D000307 | Adrenal Gland Diseases |
| D004700 | Endocrine System Diseases |
| D004701 | Endocrine Gland Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D007029 | Hypothalamic Neoplasms |
| D015173 | Supratentorial Neoplasms |
| D001932 | Brain Neoplasms |
| D016543 | Central Nervous System Neoplasms |
| D009423 | Nervous System Neoplasms |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D007027 | Hypothalamic Diseases |
| D010900 | Pituitary Diseases |
| D006964 | Hyperpituitarism |
Not provided
Not provided
| ID | Term |
|---|---|
| C517782 | pasireotide |
| D000077465 | Cabergoline |
| ID | Term |
|---|---|
| D004873 | Ergolines |
| D004876 | Ergot Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
Not provided
Not provided
| Death |
|
| Protocol Violation |
|
| Native American |
|
| Black |
|
| Other |
|
| Moderate |
|
| Severe |
|
| Not done |
|
| Moderate |
|
| Severe |
|
| Not done |
|
| Moderate |
|
| Severe |
|
| Not done |
|
| Moderate |
|
| Severe |
|
| Not done |
|
| Moderate |
|
| Severe |
|
| Not done |
|
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| Participants |
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