Efficacy and Safety of Pasireotide LAR (Long-acting Release) in Japanese Patients With Acromegaly or Pituitary Gigantism

Study Overview
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Brief Summary
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To evaluate efficacy, safety, pharmacokinetics and pharmacodynamics of pasireotide LAR in Japanese patients with active acromegaly or pituitary gigantism. Primary objective was to assess the total-group efficacy of pasireotide LAR on the reduction of mean GH levels to < 2.5 µg/L and the normalization of insulin-like growth factor-1 (IGF-1) at 3 months of study treatment.

Official Title
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A Multicenter, Open-label, Randomized, Phase II Study to Evaluate Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Pasireotide LAR in Japanese Patients With Active Acromegaly or Pituitary Gigantism

Conditions
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Acromegaly, Pituitary Gigantism

Intervention / Treatment
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* Drug: Pasireotide LAR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with medication naïve acromegaly or pituitary gigantism Patients with inadequately controlled acromegaly or pituitary gigantism Exclusion Criteria: Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1c >8% Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block or a history of acute myocardial infarction within the six months preceding enrollment Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF > 470 ms, hypokalemia, hypomagnesemia, hypocalcemia, family history of long QT syndrome, or patients receiving a concomitant medication known to prolong QT interval

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pasireotide LAR 20mg<br>Enrolled patients were randomized to 20mg pasireotide LAR. | Drug: Pasireotide LAR<br>* Intramuscular administration of pasireotide LAR was repeated every month (1 month = 28 days) for 12 months in core phase. It was permitted to increase the dose up to 60 mg in a patient showing the following biochemical test results after 3 and 6 months of study treatment: mean GH levels ≥2.5 µg/L and/or IGF-1 > ULN. In the event of any problem with tolerability, it was permitted to reduce the next lower dosage level at any time.<br>* Other names: SOM230;|
| Experimental: Pasireotide LAR 40mg<br>Enrolled patients were randomized to 40mg pasireotide LAR. | Drug: Pasireotide LAR<br>* Intramuscular administration of pasireotide LAR was repeated every month (1 month = 28 days) for 12 months in core phase. It was permitted to increase the dose up to 60 mg in a patient showing the following biochemical test results after 3 and 6 months of study treatment: mean GH levels ≥2.5 µg/L and/or IGF-1 > ULN. In the event of any problem with tolerability, it was permitted to reduce the next lower dosage level at any time.<br>* Other names: SOM230;|
| Experimental: Pasireotide LAR 60mg<br>Enrolled patients were randomized to 60mg pasireotide LAR. | Drug: Pasireotide LAR<br>* Intramuscular administration of pasireotide LAR was repeated every month (1 month = 28 days) for 12 months in core phase. It was permitted to increase the dose up to 60 mg in a patient showing the following biochemical test results after 3 and 6 months of study treatment: mean GH levels ≥2.5 µg/L and/or IGF-1 > ULN. In the event of any problem with tolerability, it was permitted to reduce the next lower dosage level at any time.<br>* Other names: SOM230;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total-group Response Rate at Month 3 | Percentage of participants with a reduction of mean growth hormone (GH) levels to < 2.5 µg/L and the normalization of insulin-like growth factor-1 (IGF-1) to within normal limits (age and sex related) at 3 months across all doses | Month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate at Month 3 by Randomized Dose Level | Percentage of participants with a reduction of mean GH levels to < 2.5 µg/L and the normalization of IGF-1 to within normal limits (age and sex related) at 3 months in each starting dose. | Month 3 | 
| GH Response at Month 3 by Randomized Dose | Percentage of participants with a reduction of mean GH levels to < 2.5 µg/L at 3 months. | Month 3 | 
| IGF-1 Response at Month 3 by Randomized Dose | Percentage of participants with the normalization of IGF-1 to within normal limits (age and sex related) at 3 months. | Month 3 | 
| Total-group Response Rate (GH & IGF-1) Over Time (Core Phase) | Percentage of participants with a reduction of mean GH levels to < 2.5 µg/L and the normalization of IGF-1 to within normal limits (age and sex related) at 3, 6, 9 and 12 months | Months 3, 6, 9 & 12 | 
| Percentage of Overall Participants With the Reduction of GH Levels to <2.5 ug/L by Visit (Core Phase) | This refers to the percentage of participants with a reduction of growth hormone (GH) response rates to <2.5 ug/L over time. | Months 3, 6, 9, 12 | 
| Percentage of Overall Participants With the Normalization of IGF-1 by Visit (Core Phase) | This refers to the percentage of participants with the normalization of insulin-like growth factor-1 (IGF-1) to within normal limits by visit. | Months 3, 6, 9, 12 | 
| Summary of Pasireotide LAR PK Parameters of Ctrough & Cmax by Randomized Dose Level | Ctrough: The trough level concentration on day 28, 3 months post 1st, 2nd and 3rd injections of Pasireotide LAR. Cmax: The maximum concentration 3 months post the 1st injection and 3rd injection of LAR. | Ctrough: Day 28 after each injection 1-3, Cmax: 3 months after injections 1 and 3 | 
| Summary of Pasireotide LAR PK Parameter of Accumulation Ratio Randomized Dose Level | The accumulation ratio was calculated as a ratio of (Ctrough day28, 3rd injection/Ctrough day28, 1st injection). | Day 28 after injections 1 and 3 | 
| Change of Tumor Volume From Baseline | This shows the change in tumor volume from baseline to month 6 and from baseline to month 12 in patients treated with pasireotide LAR. | Baseline, Months 6 , 12 | 
| Change in Mean GH Levels From Baseline | This shows the change in mean GH levels from baseline in median GH levels by visit. | Baseline, Months 2.75, 3, 6, 9, 12, 18, 24 | 
| Change in Ring Size From Baseline | Change of clinical signs from baseline: ring size. In Japan, ring sizes are specified using a numerical scale, that only has whole sizes, and does not have simple linear correlation with diameter or circumference. Only numbers are used ranging from 1 to 27. For instance, a ring size of 1 in Japan is equivalent to an inside circumference ring size of 38.86 mm and a ring size of 27 in Japan is equivalent to an inside circumference ring size of 70.15 mm. | Baseline, Months 3, 6, 9, 12 | 
| Number of Participants With Acromegaly Symptoms or Pituitary Gigantism (Core Phase) | Number of participants with a change of clinical signs from baseline (BL): headache (HA), fatigue (FA), perspiration (PE), paresthesias (PA), osteoarthralgia (OS) | 12 Months (Core phase) | 
| Change From Baseline in Prolactin | Change in prolactin levels from baseline | Baseline, Months 3, 6, 9, 12 | 
| Total-group Response Rate by Visit (Extension Phase) | Percentage of participants with a reduction of mean GH levels to < 2.5 µg/L and the normalization of IGF-1 to within normal limits (age and sex related) a18 and 24 months of study treatment. | Months 18, 24 | 
| Percentage of Overall Participants With the Reduction of Mean GH Levels to <2.5 ug/L by Visit (Extension Phase) | Percentage of participants with a reduction of mean GH levels to < 2.5µg/L at 18 and 24 months of study treatment | Months 18, 24 | 
| Percentage of Overall Participants With the Normalization of IGF-1 by Visit (Extension Phase) | Percentage of participants with the normalization of IGF-1 to within normal limits (age and sex related) at 18 and 24 months of study. treatment | Months 18, 24 | 
| Change From Baseline in Mean GH by Visit and SSA Uncontrolled Status (Extension Phase) | This shows a change of mean GH levels and somatostatin analogues (SSAs) from baseline in extension phase | Baselnine, Months 2.75, 3, 6, 9, 12, 18, 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SOM230, Pasireotide, acromegaly, Phase II, growth disorder, gigantism, Pituitary adenoma, pituitary gigantism