Safety, Tolerability, and Efficacy of IONIS-GHR-LRx in Participants With Acromegaly Being Treated With Long-acting Somatostatin Receptor Ligands

Study Overview
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Brief Summary
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The purpose of this study was to assess the safety, tolerability, and efficacy of IONIS-GHR-LRx in up to 60 participants with acromegaly.

Detailed Description
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This short-term study assessed changes in serum insulin-like growth factor 1 (IGF-1) over a 16-week treatment period in a participant population diagnosed with acromegaly being treated with long-acting somatostatin receptor ligands (SRL).

Official Title
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A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, Tolerability, and Efficacy of ISIS 766720 (IONIS-GHR-LRx, an Antisense Inhibitor of the Growth Hormone Receptor) Administered Once Every 28 Days for 16 Weeks in Patients With Acromegaly Being Treated With Long-acting Somatostatin Receptor Ligands (SRL)

Conditions
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Acromegaly

Intervention / Treatment
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* Drug: IONIS-GHR-LRx
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females with documented diagnosis of acromegaly, aged 18-75 years old (inclusive) at the time of informed consent Participants must be on stable maximum or maximally tolerated dose of SRL (Lanreotide Autogel or Octreotide LAR, per treating physician judgment) every 28 days for a minimum of 3 months prior to screening and will be required to continue their stable dose of SRL throughout the study. Prior use of other medications for treating acromegaly is allowed but not within 6 weeks of screening. At Screening, serum insulin-like growth factor 1 (IGF-1) (performed at central lab) between 1.3 to 5 x upper limit of normal (ULN), inclusive, adjusted for age and sex Females must be non-pregnant and non-lactating, and either surgically sterile, post-menopausal, abstinent, or using 1 highly effective method of birth control Exclusion Criteria: Participants who received surgery for pituitary adenoma within the last 6 months before the trial, or planning to receive surgery during the trial Participants who received radiotherapy for pituitary adenoma within the last 3 years before the trial, and/or planning to receive radiotherapy during the trial Participants with pituitary tumor that, per Investigator judgement, is worsening as assessed by pituitary/sellar magnetic resonance imaging (MRI) protocol at Screen or within 6 months of screening Evidence of decompensated cardiac function per medical judgement and/or New York Heart Association (NYHA) class 3 or 4 Clinical evidence of symptomatic hyperprolactinemia that would necessitate treatment Participants may not have chronic systemic use of glucocorticoids, weight loss medications or participate in weight loss programs within 2 months before randomization and during study participation. Participants on anti-diabetes medication or estrogen containing medications must be on a stable dose and regimen for >= 3 months prior to screening and throughout the trial Participants taking glucagon-like peptide 1 (GLP-1) agonists or insulin can be allowed with prior consultation with the Sponsor Medical Monitor

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received placebo by subcutaneous injection (SC) once every 4 weeks for 16 weeks. | Drug: Placebo<br>* Placebo administered subcutaneously.<br>|
| Experimental: Cohort A: IONIS GHR-LRx, 60 mg<br>Participants received IONIS GHR-LRx, 60 milligrams (mg), SC, once every 4 weeks for 16 weeks. | Drug: IONIS-GHR-LRx<br>* IONIS GHR-LRx administered subcutaneously.<br>|
| Experimental: Cohort B: IONIS GHR-LRx, 80 mg<br>Participants received IONIS GHR-LRx, 80 mg, SC, once every 4 weeks for 16 weeks. | Drug: IONIS-GHR-LRx<br>* IONIS GHR-LRx administered subcutaneously.<br>|
| Experimental: Cohort C: IONIS GHR-LRx, 120 mg<br>Participants received IONIS GHR-LRx, 120 mg, SC, once every 4 weeks for 16 weeks. | Drug: IONIS-GHR-LRx<br>* IONIS GHR-LRx administered subcutaneously.<br>|
| Experimental: Cohort D: IONIS GHR-LRx, 160 mg<br>Participants received IONIS GHR-LRx, 160 mg, SC, once every 4 weeks for 16 weeks. | Drug: IONIS-GHR-LRx<br>* IONIS GHR-LRx administered subcutaneously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Serum Insulin-like Growth Factor-1 (IGF-1) From Baseline to 28 Days After Last Dose | IGF-1 is a hormone that manages the effects of growth hormone (GH) in the body. Percent change from Baseline in IGF-1 levels was measured at Day 141. Baseline was defined as the last non-missing value prior to the first administration of Study Drug (ISIS 766720 or placebo). A negative percent change from Baseline indicated improvement. To perform a meaningful assessment of the pharmacodynamic (PD) activity of ISIS 766720, the lower dose groups (60 mg and 80 mg) and higher dose groups (120 mg and 160 mg) were combined to achieve group size of 7 or more for PD assessments and these were designated as low-dose and high-dose groups respectively. | Baseline and 28 days after last dose (Day 141) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | A TEAE was defined as an adverse event that occurred after the initiation of study drug dosing and before the end of the follow-up period. | Up to 211 days | 
| Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Vitals signs included blood pressure, heart rate, respiratory rate, and temperature recorded throughout the study. Clinical significance was determined by the investigator. | Up to 211 days | 
| Number of Participants With TEAEs Related to Clinically Significant Physical Examination Findings | Physical examination included weight and body mass index (BMI) recorded throughout the study. Clinical significance was determined by the investigator. | Up to 211 days | 
| Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Clinical laboratory assessments included clinical chemistry, hematology, and urinalysis. Clinically-significant abnormal laboratory values were reported as TEAEs if the results may, in the opinion of the Investigator, constitute or be associated with an AE. | Up to 211 days | 
| Number of Participants With TEAEs Related to Clinically Significant Electrocardiogram (ECG) Findings | ECG assessments included QT, QRS duration, PR interval, ventricular rate, QTcB, QTcF. | Up to 211 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Normalized IGF-1 Levels to Within 1.2 Times of Gender and Age Limits at 28 Days After Last Dose | Normalization of circulating IGF-1 is a validated marker for the treatment of acromegaly. IGF-1 assessments were based on a single serum sample taken in fasting conditions, prior to the study drug administration. Normal IGF-1 levels for a participant differ based on age and gender. Number of participants with a normal IGF-1 level which were 1.2 times within gender and age limits after 28 days of the last dose (Day 141) are presented. To perform a meaningful assessment of the pharmacodynamic activity of ISIS 766720, the lower dose groups (60 mg and 80 mg) and higher dose groups (120 mg and 160 mg) were combined to achieve group size of 7 or more for PD assessments and these were designated as low-dose and high-dose groups respectively. | Baseline to 28 days after last dose (Day 141) | 
| Number of Participants Achieving Normalized IGF-1 Levels to Within 1.0 Times of Gender and Age Limits at 28 Days After Last Dose | Normalization of circulating IGF-1 is a validated marker for the treatment of acromegaly. IGF-1 assessments were based on a single serum sample taken in fasting conditions, prior to the study drug administration. Normal IGF-1 levels for a participant differ based on age and gender. Number of participants with a normal IGF-1 level which were 1.0 times within gender and age limits after 28 days of the last dose (Day 141) are presented. To perform a meaningful assessment of the pharmacodynamic activity of ISIS 766720, the lower dose groups (60 mg and 80 mg) and higher dose groups (120 mg and 160 mg) were combined to achieve group size of 7 or more for PD assessments and these were designated as low-dose and high-dose groups respectively. | Baseline to 28 days after last dose (Day 141) | 
| Change From Baseline in Serum IGF-1 Over Time | IGF-1 is a hormone that manages the effects of GH in the body. Change from Baseline in IGF-1 levels was measured at multiple timepoints up to Day 211. Baseline was defined as the last non-missing value prior to the first administration of Study Drug (ISIS 766720 or placebo). A negative change from Baseline indicated improvement. To perform a meaningful assessment of the pharmacodynamic activity of ISIS 766720, the lower dose groups (60 mg and 80 mg) and higher dose groups (120 mg and 160 mg) were combined to achieve group size of 7 or more for PD assessments and these were designated as low-dose and high-dose groups respectively. | Baseline, Days 15, 29, 43, 57, 71, 85, 99, 112, 127, 141, 155, 183, and 211 | 
| Percent Change From Baseline in Serum IGF-1 Over Time | IGF-1 is a hormone that manages the effects of GH in the body. Percent change from Baseline in IGF-1 levels was measured at multiple timepoints up to Day 211. Baseline was defined as the last non-missing value prior to the first administration of Study Drug (ISIS 766720 or placebo). A negative percent change from Baseline indicated improvement. To perform a meaningful assessment of the pharmacodynamic activity of ISIS 766720, the lower dose groups (60 mg and 80 mg) and higher dose groups (120 mg and 160 mg) were combined to achieve group size of 7 or more for PD assessments and these were designated as low-dose and high-dose groups respectively. | Baseline, Days 15, 29, 43, 57, 71, 85, 99, 112, 127, 155, 183, and 211 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acromegaly, IONIS-GHR-LRx