Nutritional and Metabolic Diseases

All Conditions

Musculoskeletal Diseases

Nervous System Diseases

Gland and Hormone Related Diseases

Neoplasms

Rare Diseases

Hyperglycemia

Acromegaly

ACTH-Secreting Pituitary Adenoma

Pituitary ACTH Hypersecretion

Adenoma

Pituitary Diseases

Metabolic Diseases

Glucose Metabolism Disorders

Bone Diseases

Bone Diseases, Endocrine

Hypothalamic Diseases

Brain Diseases

Central Nervous System Diseases

Endocrine System Diseases

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Pituitary Neoplasms

Endocrine Gland Neoplasms

ACTH-secreting Pituitary Adenoma

Hypoglycemic Agents

All Drugs and Chemicals

Anti-Infective Agents

Gastrointestinal Agents

Metformin

Liraglutide

Insulin

Insulin, Globin Zinc

Incretins

Sitagliptin Phosphate

Pasireotide

Somatostatin

Hormones

Hormone Antagonists

Dipeptidyl-Peptidase IV Inhibitors

HIV Protease Inhibitors

Protease Inhibitors

Enzyme Inhibitors

Glucagon

Glucagon-Like Peptide-1 Receptor Agonists

Glucagon-Like Peptide 1

Participants randomized to the incretin based arm started with sitagliptin once daily. If sitagliptin did not control the participant's hyperglycemia, sitagliptin was stopped and participants switched to liraglutide once daily. If despite treatment with liraglutide, hyperglycemia was not controlled then the participant was eligible for rescue therapy with addition of insulin.

Participants randomized to the insulin arm started with once daily dose of basal insulin. The dose was up or down titrated at the discretion of the investigator. If blood glucose levels remained uncontrolled on basal insulin, participant switched to basal insulin plus prandial insulin.

This arm represents the non-randomized participants: Cushing's Disease (CD) or Acromegaly participants, who received pasireotide s.c. or LAR (long-acting release) respectively, but who were not randomized to the Incretin or Insulin arms.

For the purpose of analysis, this non-randomized arm is further split into 3 groups:

* Baseline insulin group (BL insulin) includes participants who were receiving insulin at study entry
* Oral antidiabetic drugs (OAD) group includes participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment
* No OAD group includes participants who did not receive any anti-diabetic medication during the core phase of the trial

Administered to Cushing's disease participants.

Pasireotide s.c.

Taken for approximately 16 weeks during the core study phase or until the drug was found not to be effective

Sitagliptin

Participant switched to liraglutide if sitagliptin was found not to be effective.

Participant took insulin for 16 weeks. Insulin was also administered as rescue therapy in the incretin-based therapy arm if required.

Insulin was administered to the BL-insulin group at the discretion of the Principal Investigator.

Note: OAD and No OAD groups within the non-randomized arm did not take Insulin.

Pasireotide LAR

If previously normo-glycemic participants experienced increase in their fasting blood glucose and meeting the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to experience increase in their fasting blood glucose within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks. Metformin treatment was not required for the BL Insulin and OAD groups, within the non-randomized arm, but may have been prescribed at the discretion of the investigator.

Note: No OAD group within the non-randomized arm did not take metformin.

Novartis Pharmaceuticals

The study was designed to investigate the optimal management of hyperglycemia developed during pasireotide treatment in participants with Cushing's disease or Acromegaly, which was not manageable with metformin.

This was a Phase IV, multi-center, randomized, open-label study. Eligible patients started pasireotide subcutaneously (s.c.) for Cushing's disease and pasireotide LAR (long-acting release) for Acromegaly.

Participants being treated with pasireotide s.c or LAR at screening were eligible as long as they met protocol criteria during the screening period. If previously normo-glycemic participants experienced an increase in their fasting blood glucose and met the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to have elevated blood glucose above target on metformin within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks.

Participants who continued to receive clinical benefit after completing the Core Phase could enter an optional Extension Phase if pasireotide was not commercially available in their country or a local access program was not available to provide drug. Patients continued in the Extension Phase until the last participant randomized in the Core Phase completed 16 weeks of treatment post-randomization.

Study of Management of Pasireotide-induced Hyperglycemia in Adult Patients With Cushing's Disease or Acromegaly

A Multi-center, Randomized, Open-label, Phase IV Study to Investigate the Management of Pasireotide-induced Hyperglycemia With Incretin Based Therapy or Insulin in Adult Patients With Cushing's Disease or Acromegaly

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

Absolute change in HbA1c from randomization to end of core phase (16 weeks) in incretin based therapy arm and insulin arm, and mean difference of change in HbA1c between the two treatment groups based on an ANOVA model using treatment (Incretin, Insulin) and the two randomization stratification factors (Disease: Cushing's disease vs Acromegaly; Baseline glycemic status: HbA1c \<7% vs HbA1c ≥ 7%) as fixed effects. For Participants who discontinued the study or required rescue treatment before the time of assessing the primary endpoint, the last HbA1c assessment collected 8 weeks (56 days) after randomization (and prior to or on the date of start of rescue treatment) was carried forward. If the participant discontinued the study or used rescue treatment within 8 weeks after randomization, it was considered missing.

Absolute change in HbA1c overtime from randomization (i.e. start of randomized antidiabetic treatment) to end of core phase per randomized arm

Absolute change in fasting glucose overtime from randomization (i.e. start of randomized antidiabetic treatment) to end of core phase per randomized arm

The percentage of participants who received anti-diabetic rescue therapy in incretin based therapy is summarized.

Absolute change in HbA1c from baseline to end of core phase in the incretin based therapy arm and the insulin arm

Absolute change in FPG from baseline to end of core phase in the incretin based therapy arm and the insulin arm.

Percentage of participants with ≤ 0.3% HbA1c increase in the incretin based therapy arm and the insulin arm.

There are different safety follow-up period for Cushing's and for acromegaly patients: On-treatment period: from day of first dose of study medication to 28 days after last dose of pasireotide s.c. and 84 days after last dose of pasireotide long acting, or the follow-up visit, whichever comes later.

Participants randomized to the incretin based arm started with sitagliptin once daily. If sitagliptin did not control the participant's hyperglycemia, sitagliptin was stopped and participants switched to liraglutide once daily. If despite treatment with liraglutide, hyperglycemia was not controlled then the participant was eligible for rescue therapy with addition of insulin

Incretin Based Therapy (Randomized Group)

Insulin (Randomized Group)

This group included participants who were receiving insulin at study entry.

Baseline Insulin (BL) (Non-randomized Group)

This group included participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment. Patients in this group did not require additional treatment with either incretin or insulin.

Oral Antidiabetic Drugs (OAD) (Non-randomized Group)

This group included participants who did not receive any anti-diabetic medication during the Core Phase of the study as they did not develop hyperglycemia.

No OAD (Non-randomized Group)

Total

Age, Continuous

Sex: Female, Male

Other

Chinese

Hispanic/Latino

Indian (Indian subcontinent)

Japanese

Race/Ethnicity, Customized

Full Analysis Set (FAS): all participants who received at least one dose of pasireotide.

Study Director

All Patients

Cushing's Disease

Randomized Analysis Set (RAS): all patients who received at least one dose of pasireotide and were assigned to either incretin based therapy or insulin by randomization.

If the patient discontinued the study or used rescue treatment within 8 weeks after randomization, it was considered missing.

Change in HbA1c From Randomization to Approximately 16 Weeks

Randomization

Change at RW4 D29

Change at RW8 D57

Change at RW12 D85

Change at RW16 D113

End of Core Phase

Randomized Analysis Set (RAS): all patients who received at least one dose of pasireotide and were assigned to either incretin based therapy or insulin by randomization.

Change in HbA1c From Randomization (R) Over Time Per Randomized Arm

Change at RW2 D15

Change at RW6 D43

Change at RW10 D71

Change at RW14 D99

Change in FPG (Fasting Plasma Glucose) From Randomization Until End of Core Phase

Safety set - All participants randomized to the incretin-based therapy who received at least one dose of pasireotide and had at least one post-baseline safety assessment. Randomized participants within the safety set were analyzed according to the anti-diabetic study treatment first received.

Percentage of Participants in the Incretin-based Arm Who Required Anti-diabetic Rescue Therapy With Insulin

Baseline: All Patients

Change at EOP: All Patients

Baseline: Cushing's

Change at EOP: Cushing's

Baseline: Acromegaly

Change at EOP: Acromegaly

Full Analysis Set (FAS): Participants who received at least 1 dose of pasireotide. Randomized participants were analyzed according to the anti-diabetic treatment assigned to at randomization. Non-randomized participants were analyzed by the anti-diabetic treatment received during the core phase (insulin at baseline, oral antidiabetics (OAD), none).

Absolute Change in HbA1c From Baseline to End of Core Phase

Full Analysis Set (FAS): All participants who received at least one dose of pasireotide. Randomized patients were analyzed according to the anti-diabetic treatment assigned to at randomization. Non-randomized patients were analyzed by the anti-diabetic treatment received during the core phase (insulin at baseline, oral antidiabetics (OAD), none).

Absolute Change in FPG From Baseline to End of Core Phase

Randomized Analysis Set (RAS): all participants who received at least one dose of pasireotide and were assigned to either incretin based therapy or insulin by randomization.

Percentage of Participants With ≤ 0.3% HbA1c Increase to End of Core Phase

Core Phase

Extension Phase

SOM230

Recordati

This is a non-interventional, multinational, multi-center post-marketing study, to further document the safety and efficacy of pasireotide s.c. administered in routine clinical practice in patients with Cushing's disease. Patients with Cushing's disease and treated with pasireotide s.c. alone and in combination with other therapies will be monitored. For this study, each enrolled patient will be followed up for 3 years after enrollment. Patients who permanently discontinue pasireotide s.c. prior to completing the 3-year observation period will be followed up for 3 months after the last dose of pasireotide s.c.

Long Term Safety and Efficacy of Pasireotide s.c. in Patients With Cushing's Disease

Non-interventional Study for the Generation of Long Term Safety and Efficacy Data of Pasireotide s.c. in Patients With Cushing's Disease (Post-Authorization Safety Study)

Number of pasireotide s.c related adverse events and serious adverse events, when administered as monotherapy or in combination with other therapies in patients with Cushing's disease

The proportion of patients with a mean UFC ≤ ULN at 1, 3, 6, 12, 24 and 36 months after enrolling into the study

The absolute and percentage change from baseline of mean UFC measures of disease activity after enrolling into the study.

Proportion of patients achieving serum cortisol Normalization of disease activity where normalization refers to being within the upper and lower limit of normal ranges

The absolute and percentage change of blood pressure from baseline after enrolling into the study

The proportion of patients with favorable shift of blood pressure from baseline after enrolling into the study

Safety parameters include: Adverse events , Serious Adverse Events, vital signs, blood pressure, heart rate, body temperature, blood glucose (fasting plasma glucose, HemoglobinA1c), hormones (IGF-1, GH, TSH/free T4), liver enzymes (AST, ALT, alkaline phosphatase, γGT, total bilirubin), hematology, electrolytes, immunological events (e.g., allergic reactions: rash, pruritus, injection site reactions), gallbladder ultrasound and ECGs. Efficacy parameters include: Urinary Free Cortisol, serum cortisol, serum cortisol after dexamethasone testing, salivary cortisol, plasma ACTH, fasting serum lipid profile, Blood pressure, body weight, body mass index, waist circumference, tumor size and quality of life.

The absolute and percentage change in tumor size after enrolling into the study

The absolute and percentage change from baseline in patient -reported outcome questionnaires (Cushing QoL and EURO QoL) after enrolling into the study

The absolute and percentage change from baseline of serum cortisol measures of disease activity after enrolling into the study

The absolute and percentage change from baseline of serum cortisol after dexamathasone testing measures of disease activity after enrolling into the study

The absolute and percentage change from baseline of salivary cortisol measures of disease activity after enrolling into the study

The absolute and percentage change from baseline of ACTH measures of disease activity after enrolling into the study

Proportion of patients achieving serum cortisol after dexamethasone testing Normalization of disease activity where normalization refers to being within the upper and lower limit of normal ranges

Proportion of patients achieving salivary cortisol of disease activity where normalization refers to being within the upper and lower limit of normal ranges

Proportion of patients achieving ACTH of disease activity where normalization refers to being within the upper and lower limit of normal ranges

The absolute and percentage change from baseline of fasting serum lipid profile measures of disease activity after enrolling into the study

The absolute and percentage change of body weight from baseline after enrolling into the study

The absolute and percentage change of body mass index from baseline after enrolling into the study

The absolute and percentage change of waist circumference from baseline after enrolling into the study

The proportion of patients with favorable shift of body weight from baseline after enrolling into the study

The proportion of patients with favorable shift of body mass index from baseline after enrolling into the study

The proportion of patients with favorable shift of waist circumference from baseline after enrolling into the study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Management of Pasireotide-induced Hyperglycemia in Adult Patients With Cushing's Disease or Acromegaly	NCT02060383	Cushing's Disea... Acromegaly	Pasireotide s.c... Sitagliptin Liraglutide Insulin Pasireotide LAR Metformin	18 Years -	Novartis
Study of Management of Pasireotide-induced Hyperglycemia in Adult Patients With Cushing's Disease or Acromegaly	NCT02060383	Cushing's Disea... Acromegaly	Pasireotide s.c... Sitagliptin Liraglutide Insulin Pasireotide LAR Metformin	18 Years -	Novartis
Long Term Safety and Efficacy of Pasireotide s.c. in Patients With Cushing's Disease	NCT02310269	Cushings Diseas...	SOM230	18 Years -	RECORDATI GROUP

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