Safety and Efficacy of Pasireotide Long Acting Release (LAR) vs. Octreotide LAR in Patients With Active Acromegaly

Study Overview
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Brief Summary
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The patients received either Pasireotide LAR or Octreotide LAR for one year of treatment. The objective of this study was to compare the proportion of patients with a reduction of mean GH level to <2.5 µg/L and the normalization of IGF-1 to within normal limits (age and sex related) between the two treatment groups (pasireotide LAR and octreotide LAR) at 12 months. Following one year of treatment patients could proceed into the study extension. Patients who did not respond to the treatment they were randomized to (based on month 12 assessment results) were switched to the other treatment arm at month 13.

Official Title
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A Multicenter, Randomized, Blinded Study to Assess Safety and Efficacy of Pasireotide LAR vs. Octreotide LAR in Patients With Active Acromegaly

Conditions
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Acromegaly

Intervention / Treatment
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* Drug: Pasireotide
* Drug: Octreotide


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with active acromegaly (based on elevated GH and IGF-1 levels) Patients who have undergone one or more pituitary surgeries, but have not been treated medically, or de-novo patients presenting a visible pituitary adenoma on MRI and who refuse pituitary surgery or for whom pituitary surgery is contraindicated Patients for whom written informed consent to participate in the study has been obtained prior to any study related activity Exclusion criteria: Patients who are being or were treated with octreotide, lanreotide, dopamine agonists or GH antagonists with the exception of a single dose of short-acting octrotide or short-acting dopamine agonists. In case of a single dose of short-acting octrotide, the dose should not be used to predict the response to the octretide treatment. The single dose of short-acting octreotide or short-acting dopamine agonists should not be administered in the 3 days prior to randomization Patients with compression of the optic chiasm causing any visual field defect Patients who have received pituitary irradiation within the last ten years prior to visit 1 Poorly controlled diabetic patients Other protocol-defined inclusion/exclusion criteria may apply

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pasireotide LAR<br>Patients in this arm received Pasireotide LAR 40 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 20 or 60 mg, respectively. Patients who responded to Pasireotide LAR (i.e. the randomized treatment) at the end of the core (Month 12), continued Pasireotide LAR treatment in the extension. Patients who did not respond to Pasireotide LAR at the end of the core (Month 12) were allowed to switch to receive Octreotide LAR in the extension. | Drug: Pasireotide<br>* Pasireotide LAR - intramuscular (i.m.) depot injection given once every 28 days.<br>* Other names: SOM230;|
| Active Comparator: Octreotide LAR<br>Patients in this arm received Octreotide LAR 20 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 10 or 30 mg, respectively. Patients who responded to Octreotide LAR (i.e. the randomized treatment) at the end of the core (Month 12) continued Octreotide LAR treatment in the extension (up to 2 years of treatment). Patients who did not respond to Octreotide LAR at the end of the core (Month 12) were allowed to switch to receive Pasireotide LAR in the extension. | Drug: Octreotide<br>* Octreotide LAR - i.m. depot injection given once every 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Reduction of Mean GH Level to <2.5 μg/L and the Normalization of IGF-1 | Percentage of participants with a reduction of mean GH levels to <2.5μg/L (based on a 5-point 2-hour profile) and normalization of sex- and age-adjusted IGF-1. Post surgery = patients with prior surgery but no previous medical treatment for acromegaly De novo = patients with de novo disease who refused pituitary surgery or for whom pituitary surgery was contraindicated. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Reduction of Mean GH Level to < 2.5μg/L | Percentage of participants with a reduction of mean GH levels to < 2.5μg/L (based on a 5-point 2-hour profile). Post surgery = patients with prior surgery but no previous medical treatment for acromegaly De novo = patients with de novo disease who refused pituitary surgery or for whom pituitary surgery was contraindicated. | 12 Months | 
| Change From Baseline in Tumor Volume at 12 Months | Absolute and percentage change from baseline in tumor volume (assessed by pituitary MRI) Post surgery = patients with prior surgery but no previous medical treatment for acromegaly De novo = patients with de novo disease who refused pituitary surgery or for whom pituitary surgery was contraindicated. | Baseline, 12 Months | 
| Percentage of Participants With Normalization of IGF-1 | Percentage of participants with normalization of sex- and age-adjusted IGF-1. Post surgery = patients with prior surgery but no previous medical treatment for acromegaly De novo = patients with de novo disease who refused pituitary surgery or for whom pituitary surgery was contraindicated. | 12 Months | 
| Percentage of Participants With a Reduction of Mean GH Level to < 2.5μg/L and Normalization of IGF-1 | Percentage of participants with a reduction of mean GH levels to < 2.5μg/L (based on a 5-point 2-hour profile) and normalization of sex- and age-adjusted IGF-1. Denominator for time points up to Month 12 is the Full Analysis Set (FAS). Denominator for time points after Month 12 excludes patients who completed the core and did not enter the extension. Patients who discontinued were considered non-responders for the time points after discontinuation, patients who crossed over were considered non-responders for all time points after crossover. Analysis was based on data up to crossover (i.e., included data from both blinded core & ext. phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included.) | Months 3, 6, 9, 12, 16, 19, 22, 25 | 
| Summary of Mean GH Values | Mean GH levels (based on a 5-point profile over 2 hours). Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). | Baseline, Months 3, 6, 9, 12, 16, 19, 22, 25 | 
| Time to First Response for Patients Achieving a Reduction of Mean GH Level to < 2.5 μg/L and Normalization of IGF-1 (No. of Responders: Pasireotite LAR = 81, Octreotide LAR = 63) ) | Time to first response for patients achieving a reduction of mean GH level to < 2.5 μg/L and normalization of IGF-1. Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). | Up to 26 months | 
| Severity Scores of Acromegaly Symptoms | Severity scores of acromegaly symptoms (Headache, Fatigue, Perspiration, Paresthesias, Osteoarthralgia). Symptoms were scored from 0 (no symptom) to 4 (very severe). Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). | Baseline, Months 12, 25 | 
| Ring Size | Ring size (based on jeweler's finger gauge). Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). | Baseline, Months 12, 25 | 
| Health-related Quality-of-life as Measured by the AcroQoL Questionnaire | Acromegalyy quality of life (AcroQoL) total scores. The AcroQoL questionnaire is unidimensional and contains 22 items divided in two scales: one that evaluates physical aspects (eight items) and another one that evaluates psychological aspects (14 items). The scoring of the questionnaire was performed as specified by the instrument developers. Total scores range from 0 to 100. Higher scores represent better quality of life. Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). | Baseline, Months 12, 25 | 
| Summary of Prolactin Levels | Prolactin Levels. Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). | Baseline, Months 12, 25 | 
| Duration of Response for Patients Achieving a Reduction of Mean GH Level to <2.5 μg/L and the Normalization of IGF-1 at Month 12 (No. of Responders: Pasireotide LAR = 51, Octreotide LAR = 32) | The duration of response is defined as the time from the date that patient first met and maintained the response criteria based on primary efficacy variable to the date that patient lost response status. Median and corresponding 95% CI are derived based on Kaplan-Meier method. Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). | Up to 26 months | 
| Pasireotide Trough Concentrations by Incident Dose | Pasireotide LAR trough concentrations by incident dose (last dose administered prior to PK sample collection). PK observations with missing concentrations, missing dose, missing elapsed time or an elapsed time from previous injection outside of 28±2 days window were excluded. 5 patients with evaluable PK data in the pasireotide arm received erroneously 20 mg pasireotide LAR at baseline. | Months 1 - 12 | 
| Octreotide Trough Concentrations by Incident Dose | Octreotide LAR trough concentrations by incident dose (last dose administered prior to PK sample collection). PK observations with missing concentrations, missing dose, missing elapsed time or an elapsed time from previous injection outside of 28±2 days window were excluded. | Months 1 - 12 | 
| Percentage of Participants With a Reduction of Mean GH Level to < 2.5μg/L and Normalization of IGF-1 After Crossover | Percentage of participants with a reduction of mean GH levels to < 2.5μg/L (based on a 5-point 2-hour profile) and normalization of sex- and age-adjusted IGF-1. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). Denominator for all time points is the Crossover Analysis Set (CAS). | Months 3, 6, 9, 12 after crossover | 
| Percentage of Participants With a Reduction of Mean GH Level to < 2.5μg/L | Percentage of participants with a reduction of mean GH levels to < 2.5μg/L (based on a 5-point 2-hour profile). Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). Denominator for time points up to Month 12 is the Full Analysis Set. Denominator for time points after Month 12 excludes patients who completed the core and did not enter the extension. Patients who discontinued were considered non-responders for the time points after discontinuation, patients who crossed over were considered non-responders for all time points after crossover. | Months 3, 6, 9, 12, 16, 19, 22, 25 | 
| Percentage of Participants With Normalization of IGF-1 | Percentage of participants with normalization of sex- and age-adjusted IGF-1. Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). Denominator for time points up to Month 12 is the FAS. Denominator for time points after Month 12 excludes patients who completed the core and did not enter the extension. Patients who discontinued were considered non-responders for the time points after discontinuation, patients who crossed over were considered non-responders for all time points after crossover. | Months 3, 6, 9, 12, 16, 19, 22, 25 | 
| Change From Baseline in Tumor Volume | Percentage change from baseline in tumor volume (assessed by pituitary MRI). Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). | Baseline, months 6, 12, 19, 25 | 
| Percentage of Participants With a Reduction of Mean GH Level to < 2.5μg/L After Crossover | Percentage of participants with a reduction of mean GH levels to < 2.5μg/L (based on a 5-point 2-hour profile). Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). Denominator for all time points is the Crossover Analysis Set (CAS). | Months 3, 6, 9, 12 after crossover | 
| Percentage of Participants With Normalization of IGF-1 After Crossover | Percentage of participants with normalization of sex- and age-adjusted IGF-1. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). Denominator for all time points is the Crossover Analysis Set (CAS). | Months 3, 6, 9, 12 after crossover | 
| Summary of Mean GH Values After Crossover | Mean GH levels (based on a 5-point profile over 2 hours). Extension baseline was defined as last measurement prior to the start of crossover treatment. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). | Extension baseline, months 3, 6, 9, 12 after crossover | 
| Change From Extension Baseline in Tumor Volume After Crossover | Percentage change from extension baseline in tumor volume (assessed by pituitary MRI). Extension baseline was defined as last assessment prior to the administration of the new treatment after crossover. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). | Extension baseline, months 6, 12 after crossover | 
| Severity Scores of Acromegaly Symptoms After Crossover | Severity scores of acromegaly symptoms (Headache, Fatigue, Perspiration, Paresthesias, Osteoarthralgia). Symptoms were scored from 0 (no symptom) to 4 (very severe). Extension baseline was defined as last measurement prior to the start of crossover treatment. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). | Extension baseline, month 12 after crossover | 
| Ring Size After Crossover | Ring size (based on jeweler's finger gauge). Extension baseline was defined as last measurement prior to the start of crossover treatment. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). BL = baseline, LH = left hand, RH = right hand, CO = crossover | Extension baseline, month 12 after crossover | 
| Health-related Quality-of-life as Measured by the AcroQoL Questionnaire After Crossover | AcroQoL total scores. The AcroQoL questionnaire is unidimensional and contains 22 items divided in two scales: one that evaluates physical aspects (eight items) and another one that evaluates psychological aspects (14 items). The scoring of the questionnaire was performed as specified by the instrument developers. Extension baseline was defined as last measurement prior to the start of crossover treatment. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). Total scores range from 0 to 100. Higher scores represent better quality of life. | Extension baseline, months 12 after crossover | 
| Summary of Prolactin Levels After Crossover | Prolactin (PRL) levels. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). Extension baseline was defined as last measurement prior to the start of crossover treatment. | Extension baseline, month 12 after crossover | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acromegaly,, adult,, growth hormone,, insulin-like growth factor I,, somatostatin analogue