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

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)

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

Study Overview

• Status: Completed
• Conditions: Acromegaly
• Intervention / Treatment: Drug: Placebo; Drug: IONIS-GHR-LRx

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• Hungary
  • Budapest, Hungary, 1062
    • Magyar Honvedseg Allami Egeszsegugyi Kozpont, II. sz Belgyogyaszat Osztaly
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Kozpont
  • Szeged, Hungary, 6720
    • Szeged University - Szent-Gyorgyi Albert Clinical Center - I. Belgyógyászati Klinika (Internal Medicine)
• Lithuania
  • Kaunas, Lithuania, 50009
    • Hospital of Lithuanian University of Health Sciences (LSMU) Kauno klinikos - Hospital of Oncology
  • Vilnius, Lithuania, 08661
    • Vaidoto Urbanaviciaus Individuali imone - Endokrinologijos klinika
• Poland
  • Chorzow, Poland, 41-500
    • B_Serwis Popenda Sp. J. Specjalistyczna Przychodnia Lekarsk
  • Katowice, Poland, 40-952
    • Uniwersyteckie Centrum Kliniczne im. Prof. K. Gibinskiego Slaskiego Uniwersytetu Medycznego w Katowicach
  • Krakow, Poland, 31-011
    • Centrum Nowoczesnych Terapii Dobry Lekarz Sp. z o. o.
  • Nowa Sol, Poland, 67-00
    • Twoja Przychodnia - Centrum Medyczne Nowa Sol
  • Warszawa, Poland, 03-242
    • Mazowiecki Szpital Brodnowski - Zespol Oddzialow Chorob Wewnetrznych, Endokrynologii i Diabetologii
  • Wroclaw, Poland, 51-162
    • Centrum Badań Klinicznych Piotr Napora Lekarze Sp. p.
• Romania
  • Bucharest, Romania, 010567
    • Centrul Medical Unirea - Bucuresti, Endocrinologie
  • Cluj-Napoca, Romania, 400349
    • Spitalul Clinic Judetean de Urgenta Cluj - Napoca
  • Targu-Mures, Romania, 540142
    • Spitalul Clinic Judetean Mures
  • Timisoara, Romania, 300723
    • Spitalul Clinic Judetean de Urgenta Timisoara
• Russian Federation
  • Barnaul, Russian Federation, 656043
    • Multi-field Medical Clinic Anturium LLC
  • Kazan, Russian Federation, 420101
    • Interregional Clinical Diagnostic Center
  • Kemerovo, Russian Federation, 650066
    • Kuzbass Clinical Hospital n.a. S.V. Belyaev
  • Moscow, Russian Federation, 117036
    • Federal State Budget Institution "National Medical Research Center of Endocrinology" of the Ministry of Healthcare of the Russian Federation
  • Moscow, Russian Federation, 119992
    • I.M. Sechenov Moscow First State Medical University
  • Novosibirsk, Russian Federation, 630087
    • Novosibirsk State Regional Clinical Hospital
  • Orenburg, Russian Federation, 460018
    • Orenburg Regional Clinical Hospital, Endocrinology Department
  • Rostov-On-Don, Russian Federation, 344022
    • Rostov State Medical University
  • St. Petersburg, Russian Federation, 194156
    • Almazov National Medical Research Centre
  • Tver, Russian Federation, 170036
    • State Budget Healthcare Institution of the Tver Region
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Center of Serbia
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham (UAB)
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital and Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Palm Research Center, Inc.
    • Las Vegas, Nevada, United States, 89128
      • Palm Research Center, Inc.
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University (OHSU)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males or females with documented diagnosis of acromegaly, aged 18-75 years old (inclusive) at the time of informed consent
2. 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.
3. 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
4. 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:

1. Participants who received surgery for pituitary adenoma within the last 6 months before the trial, or planning to receive surgery during the trial
2. Participants who received radiotherapy for pituitary adenoma within the last 3 years before the trial, and/or planning to receive radiotherapy during the trial
3. 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
4. Evidence of decompensated cardiac function per medical judgement and/or New York Heart Association (NYHA) class 3 or 4
5. Clinical evidence of symptomatic hyperprolactinemia that would necessitate treatment
6. 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.
7. 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
8. Participants taking glucagon-like peptide 1 (GLP-1) agonists or insulin can be allowed with prior consultation with the Sponsor Medical Monitor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): September 13, 2018
• Primary Completion (Actual): February 18, 2021
• Study Completion (Actual): April 2, 2021

Study Registration Dates

• First Submitted: May 22, 2018
• First Submitted That Met QC Criteria: June 5, 2018
• First Posted (Actual): June 7, 2018

Study Record Updates

• Last Update Posted (Actual): November 14, 2022
• Last Update Submitted That Met QC Criteria: October 21, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Acromegaly, IONIS-GHR-LRx
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Musculoskeletal Diseases; Hypothalamic Diseases; Bone Diseases; Bone Diseases, Endocrine; Hyperpituitarism; Pituitary Diseases; Acromegaly
• Other Study ID Numbers: ISIS 766720-CS2; 2017-004259-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No