Pasireotide in Patients With Acromegaly Inadequately Controlled With First Generation Somatostatin Analogues

Study Overview
=================
Brief Summary
-----------------
This is a phase IIIb multicenter, open-label; single arm study to evaluate the efficacy and safety of pasireotide LAR 40 mg and 60 mg in patients with inadequately controlled acromegaly with maximal approved doses of first generation somatostatin analogues. The study will enroll inadequately controlled patients by high doses (maximal approved) of first-generation somatostatin analogues given for at least 3 months. Patients will receive pasireotide LAR 40 mg or 60 mg during the 36 week core study phase. Patients who have completed all visits of core phase and have completed all the assessments at the core phase completion visit can move into the 32-week extension phase. Patients can continue with study treatment until pasireotide LAR is commercially available and reimbursed in their respective country or until the end of the extension phase whichever occurs first.

Detailed Description
-----------------
This is a phase IIIb multicenter, open-label; single arm study to evaluate the efficacy and safety of pasireotide LAR 40 mg and 60 mg in patients with inadequately controlled acromegaly with maximal doses of first generation somatostatin analogues. The study will enroll inadequately controlled patients by high doses of first-generation somatostatin analogues given for at least 3 months. Patients will be categorized into two groups. Group 1 consists of patients treated with octreotide LAR 30 mg from countries where octreotide LAR 40mg is approved for the treatment of acromegaly at the time of screening. These patients will start a 3-months run-in phase to receive 40mg octreotide before being considered eligible to enter the core treatment phase. After 3 months of treatment have been completed, and prior to the fourth injection a mean GH and IGF-1 will be assessed. Patients who are achieving biochemical control will be considered a screen failure and they will not qualify for the core phase of the study. They will continue treatment with octreotide LAR 40 mg outside the frame of this study. Group 2 consists of patients treated with octreotide LAR 30 mg from countries where octreotide 40mg is NOT yet approved at the time of screening. This group also includes patients already treated with octreotide LAR 40 mg or lanreotide ATG 120 mg. Patients should have been treated with the first generation SSAs for at least 3 months prior to screening. Eligible patients can directly enter the core treatment phase of the study. A run-in phase is not required for this patient population. In the core treatment phase patients will start treatment with pasireotide LAR 40 mg every 4 weeks. At week 12, the mean GH value and IGF-1value will be assessed. Patients who have not achieved biochemical control by week 12 and do not have any tolerability issues with pasireotide LAR 40 mg will have the dose increased to 60 mg. Patients who have achieved biochemical control by week 12 will maintain a dose of pasireotide LAR 40 mg. A mean GH value and IGF-1 value will be assessed every 12 weeks until Visit 777. At weeks 16 and 28, the investigator will be able to adjust the dose based on the achievement of biochemical control and drug tolerability. If tolerability issues occur, the dose can be decreased in 20 mg. Once the tolerability issue resolves, the patients should return to the dose previously received. Patients will be treated for a total of 36 weeks during the core phase. During this period any concomitant medication for the treatment of acromegaly is prohibited. Patients are required to complete a core phase completion visit 4 weeks after the last dose of pasireotide LAR is administered. Patients who discontinue from the core phase are also required to complete the core phase completion visit 4 weeks after receiving the last pasireotide LAR dose. Patients who have completed all visits of core phase and have completed all the assessments at the core phase completion visit (Visit 777) can move into the extension phase. The core phase completion visit performed at Visit 777, will also be the first visit (Visit 18) of the extension phase. At Visit 18, the patients will receive the same dose of pasireotide LAR that they received at week 32 (Visit 17). At week 40 (Visit 19), the investigator will decide the treatment regimen and the pasireotide LAR dose based on the achievement of biochemical control at Visit 777. Patients achieving biochemical control at the end of the core phase will continue pasireotide LAR monotherapy at the same dose of the core phase. Patients who are uncontrolled at the end of the core phase will continue pasireotide LAR 60 mg and they will be allowed to receive concomitant treatment with medications used to treat acromegaly based on the investigator's clinical judgment. GH and IGF-1 levels will be assessed every 12 weeks until week 72. At weeks 52 and 64, the investigator will be able to adjust the dose of pasireotide LAR and the regimen of the concomitant medication used to acromegaly based on the patients achievement of biochemical control and drug tolerability. Patients will be treated for a total of 32 weeks in the extension phase and receive the last dose of study treatment at week 68 (Visit 26). Patients are required to complete an extension phase completion visit (Visit 778) 4 weeks after the last dose of pasireotide LAR is administered. Patients who prematurely discontinue from the extension phase are also required to complete the extension phase completion visit (Visit 778) 4 weeks after receiving the last dose of pasireotide LAR. After discontinuation from the study or completion of study treatment either at the core phase or extension phase of the study, all patients will be followed for safety for 12 weeks (84 days) after the last study drug administration. This visit can be performed by phone, a study visit for follow-up is not mandatory.

Official Title
-----------------
A Phase IIIb Multicenter, Open-label, Single Arm Study to Evaluate the Efficacy and Safety of Pasireotide in Patients With Acromegaly Inadequately Controlled With First Generation Somatostatin Analogues

Conditions
-----------------
Acromegaly

Intervention / Treatment
-----------------
* Drug: Pasireotide LAR


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent Male and female patients ≥18 years Patients with confirmed diagnosis of inadequately controlled acromegaly (mean GH concentration ≥1 μg/L and sex- and age-adjusted IGF-1 >1.3 x ULN) Patients treated with octreotide LAR (30 mg or 40 mg) or lanreotide ATG (120 mg) monotherapy for at least 3 months prior to screening Exclusion Criteria: Concomitant treatment with other medications reducing GH and or IGF-1, unless discontinued 3 months prior to screening Patients with compression of the optic chiasm requiring surgical intervention Diabetic patients with HbA1c >8% at screening Patients who are hypothyroid and not on adequate replacement therapy Patients with symptomatic cholelithiasis and acute or chronic pancreatitis Patients with clinically significant valvular disease Patients with risk factors for torsade de pointes (TdP) Hypokalaemia, hypomagnesaemia, uncontrolled hypothyroidism, family history of long QT syndrome or concomitant medications with known risk of TdP Patients with congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, history of acute MI less than one year prior to study entry or clinically significant impairment in cardiovascular function. Concomitant disease(s) that could prolong the QT interval such as autonomic neuropathy (caused by diabetes or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or cardiac failure Patients with liver disease or ALT/AST > 2.0 X ULN, serum bilirubin >2.0 X ULN - Presence of Hepatitis B surface antigen or Hepatitis C antibody test Patients with serum creatinine >2.0 X ULN Patients with WBC <3 X 109/L; Hb 90% < LLN; PLT <100 X 109/L Patients with active or suspected acute or chronic uncontrolled infection Patients who have undergone major surgery/surgical therapy within 4 weeks prior to screening Patients with active malignant disease within the last five years (with the exception of basal cell carcinoma or carcinoma in situ of the cervix) Patients with abnormal coagulation (PT and/or APTT elevated by 30% above normal limits) or patients receiving anticoagulants that affect PT (prothrombin time) or APTT (activated partial thromboplastin time) History of syncope or family history of idiopathic sudden death History of immunocompromise, including a positive HIV test result (ELISA and Western blot) Known hypersensitivity to somatostatin analogues or any other component of pasireotide LAR Patients who have a history of alcohol or drug abuse in the 6 month period prior to receiving pasireotide Patients who have given a blood donation (of 400 ml or more) within 2 months before receiving pasireotide Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to dosing Patients with any current or prior medical condition interfering with the conduct of the study or the evaluation of the study results Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study. Sexually active males unless they use a condom during intercourse while taking drug and for 3 months following last dose of pasireotide Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and 3 months following the last dose of pasireotide.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pasireotide LAR<br>Patients who qualify for the core phase of the study will be treated with pasireotide LAR 40 mg initially. Patients not achieving biochemical control can be up-titrated to pasireotide LAR 60 mg. | Drug: Pasireotide LAR<br>* Pasireotide 40 mg and 60 mg. Pasireotide 20 mg which was allowed for dose decrease in case of adverse event.<br>* Other names: SOM230;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Phase: Percentage of Participants With Mean GH < 1 g/L and IGF-1 < ULN at Week 36 by Previous Treatment and Overall | Percentage of participants who achieved biochemical control defined as GH <1μg/L and IGF-1 <ULN at week 36. | Week 36 | 
| Core Phase: Percentage of Participants With Mean GH < 1 g/L and IGF-1 < ULN at Week 36 for Participants Up-titrated to Pasireotide LAR 60 mg | Percentage of participants who achieved biochemical control defined as GH <1μg/L and IGF-1 <ULN at week 36, for participants who had been up-titrated with pasireotide LAR 60 mg. | Week 36 | 
| Core Phase: Percentage of Participants With Mean GH < 1 g/L and IGF-1 < ULN at Week 36 | Percentage of participants who achieved biochemical control defined as GH <1μg/L and IGF-1 <ULN at week 36. | Wek 36 | 
| Core Phase: Percentage of Participants With Mean GH < 1 g/L and IGF-1 < ULN at Week 36 | Percentage of patients who achieved biochemical control defined as GH <1μg/L and IGF-1 <ULN at week 36, by previous treatment, type of therapy and overall. | Week 36 | 
| Core Phase: Percentage of Participants With Mean GH < 1 g/L and IGF-1 < ULN at Week 36 Overall by Baseline Diabetic Status | Percentage of participants who achieved biochemical control defined as GH <1μg/L and IGF-1 <ULN at week 36, overall by baseline diabetic status. | Week 36 | 
| Core Phase: Percentage of Participants With Mean GH < 1 g/L and IGF-1 < ULN at Week 36 by Previous Treatment and Overall - LOCF | Percentage of participants who achieved biochemical control defined as GH <1μg/L and IGF-1 <ULN at week 36, by previous treatment and overall - last observation carried forward (LOCF) | Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Phase: Change in Mean Growth Hormone (GH) Values From Baseline to Week 36 | Core phase - Changes in mean GH from study baseline to week 36. | Baseline, week 36 | 
| Core Phase: Change in Standardized IGF-1 Values From Baseline to Week 36 | Core phase - Changes in standardized IGF-1 from study baseline to week 36. | Baseline, week 36 | 
| Core Phase: Percentage of Participants With Mean GH <1 μg/L and IGF-1 <ULN | Percentage of participants achieving GH <1 μg/L and IGF-1 <ULN at weeks 12 and 24 overall and by GH level at screening. | Week 12, Week 24, Week 36 | 
| Core Phase: Percentage of Participants With IGF-1 <ULN Overall by GH Level at Screening | Percentage of participants achieving IGF-1 <ULN at weeks 12, 24 & 36. | Weeks 12, 24 & 36 | 
| Core Phase: Percentage of Participants With Mean GH <1 μg/L and IGF-1 <ULN Overall by Baseline Diabetic Status | Core phase - Percentage of patients achieving GH <1μg/L at week 12, 24, 36 overall and by GH level at screening. | Weeks 12, 24 & 36 | 
| Core Phase: Change From Baseline in Scores as Measured by Acromegaly Quality of Life (AcroQoL) | Evaluation of effect of pasireotide LAR on Health Related Quality of Life (HRQoL) was assessed using AcroQoL, an acromegaly-specific quality of life instrument. The AcroQol instrument is comprised of 22 questions divided into two scales: one evaluating physical aspects (8 items) and the other that addresses psychological aspects (14 items). The psychological scale can also be further divided into subscale that evaluates physical appearance and the other subscale focused on the impact of the disease on personal relationships of the patient (7 items each). Each of the questions has a 5-item Likert scale. For each dimension the scores range from 0-4 with 0 being the lowest impact and 4 being the most severe. | Baseline, Weeks 12, 24 & 36 | 
| Core Phase: Percentage of Participants Reporting Levels 0 - 4 by Dimensions of Acromegaly Symptoms | Symptoms of acromegaly were collected at various visits. The measurement was to be provided on a scale of 1-15 including half sizes. Investigators asked the participants to score the following symptoms of acromegaly: headache, fatigue, perspiration, paresthesias, osteoarthralgia according to a five-point score scale (0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe). | Weeks 12, 24 & 36 | 
| Core Phase: Percentage of Participants With Acromegaly Shift Symptoms From Baseline to Most Extreme Post-baseline | Symptoms of acromegaly were collected at various visits. The measurement was to be provided on a scale of 1-15 including half sizes. Investigators asked the participants to score the following symptoms of acromegaly: headache, fatigue, perspiration, paresthesias, osteoarthralgia according to a five-point score scale (0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe). | Weeks 12, 24 & 36 | 
| Core Phase: Change From Baseline in EQ-5D-5L Index Scores | Evaluation of effect of pasireotide LAR on health status, measured by EQ-5D-5L, a valid and reliable instrument for measuring general health status. The EQ-5D-5L consists of 2 pages - the descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the respondent's self-rated health on a 20-cm vertical, visual analogue scale with endpoints labeled 'the best health you can imagine' and 'the worst health you can imagine'. This scale is numbered from 0 to 100. 100 means the best health you can imagine. 0 means the worst health you can imagine. | Baseline, Weeks 12, 24 & 36 | 
| Core Phase: Change From Baseline in EQ-5D-5L VAS Assessment | Evaluation of effect of pasireotide LAR on health status, measured by EQ-5D-5L, a valid and reliable instrument for measuring general health status. The EQ-5D-5L consists of 2 pages - the descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the respondent's self-rated health on a 20-cm vertical, visual analogue scale with endpoints labeled 'the best health you can imagine' and 'the worst health you can imagine'. This scale is numbered from 0 to 100. 100 means the best health you can imagine. 0 means the worst health you can imagine. | Baseline, Weeks 12, 24 & 36 | 
| Extension Phase: Percentage of Participants With Mean GH < 1 μg/L and IGF-1 < ULN at Weeks 48, 60 & 72 (Up-titrated to Pasireotide LAR 60 mg) | Percentage of patients achieving IGF-1 <ULN at weeks 48, 60 & 72 for participants with up-titrated to Pasireotide LAR 60 mg mg | Weeks 48, 60 & 72 | 
| Extension Phase: Percentage of Participants With Mean GH < 1 μg/L and IGF-1 < ULN at Weeks 48, 60 and 72 (Overall by Baseline Diabetic Status) | Percentage of participants achieving IGF-1 <ULN at week 46, 60 and 72 overall by baseline diabetic status | Weeks 48, 60, 72 | 
| Extension Phase: Percentage of Participants With Mean GH < 1 μg/L at Weeks 48, 60, 72 and Overall, Pasireotide Montherapy and Pasireotide With Concomittant Medication and by GH Level at Screening | Percentage of patients achieving GH <1 μg/L and IGF-1 <ULN at week 48 by treatment with pasireotide LAR alone or with concomitant medications used to treat acromegaly | Weeks 48, 60, 72 | 
| Extension Phase: Change From Baseline in Scores as Measured by Acromegaly Quality of Life (AcroQoL) | Evaluation of effect of pasireotide LAR on Health Related Quality of Life (HRQoL) was assessed using AcroQoL, an acromegaly-specific quality of life instrument. The AcroQol instrument is comprised of 22 questions divided into two scales: one evaluating physical aspects (8 items) and the other that addresses psychological aspects (14 items). The psychological scale can also be further divided into subscale that evaluates physical appearance and the other subscale focused on the impact of the disease on personal relationships of the patient (7 items each). Each of the questions has a 5-item Likert scale. For each dimension the scores range from 0-4 with 0 being the lowest impact and 4 being the most severe. | Baseline, Weeks 48, 60 & 72 | 
| Extension Phase: Percentage of Participants Reporting Levels 1 - 5 by Dimensions of Acromegaly Symptoms | Symptoms of acromegaly were collected at various visits. The measurement was to be provided on a scale of 1-15 including half sizes. Investigators asked the participants to score the following symptoms of acromegaly: headache, fatigue, perspiration, paresthesias, osteoarthralgia according to a five-point score scale (0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe). | Weeks 48, 60 & 72 | 
| Extension (Ext.) Phase: Percentage of Participants With Acromegaly Shift Symptoms From Extension Baseline to Most Extreme Post-extension Baseline | Symptoms of acromegaly were collected at various visits. The measurement was to be provided on a scale of 1-15 including half sizes. Investigators asked the participants to score the following symptoms of acromegaly: headache, fatigue, perspiration, paresthesias, osteoarthralgia according to a five-point score scale (0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe). | Weeks 48, 60 & 72 | 
| Extension Phase: Change From Baseline in EQ-5D-5L Index Scores | Evaluation of effect of pasireotide LAR on health status, measured by EQ-5D-5L, a valid and reliable instrument for measuring general health status. The EQ-5D-5L consists of 2 pages - the descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the respondent's self-rated health on a 20-cm vertical, visual analogue scale with endpoints labeled 'the best health you can imagine' and 'the worst health you can imagine'. This scale is numbered from 0 to 100. 100 means the best health you can imagine. 0 means the worst health you can imagine. | Baseline, Weeks 48, 60 & 72 | 
| Extension Phase: Change From Baseline in EQ-5D-5L VAS Assessment | Evaluation of effect of pasireotide LAR on health status, measured by EQ-5D-5L, a valid and reliable instrument for measuring general health status. The EQ-5D-5L consists of 2 pages - the descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the respondent's self-rated health on a 20-cm vertical, visual analogue scale with endpoints labeled 'the best health you can imagine' and 'the worst health you can imagine'. This scale is numbered from 0 to 100. 100 means the best health you can imagine. 0 means the worst health you can imagine. | Baseline, Weeks 48, 60 & 72 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
acromegaly, GH, IGF-1, pasireotide LAR, SOM230, first generation, somatostatin analogues, growth disorder, gigantism, Pituitary adenoma, pituitary gigantism