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

Acromegaly Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03548415
• Other study ID #: ISIS 766720-CS2
• Secondary ID: 2017-004259-22
• Status: Completed
• Phase: Phase 2
• Start date: September 13, 2018
• Est. completion date: April 2, 2021

Study information

• Verified date: October 2022
• Source: Ionis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: April 2, 2021
• Est. primary completion date: February 18, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Acromegaly

Intervention

Drug:
• IONIS-GHR-LRx
IONIS GHR-LRx administered subcutaneously.
• Placebo
Placebo administered subcutaneously.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Hungary,  Lithuania,  Poland,  Romania,  Russian Federation,  Serbia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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)
Secondary	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)
Secondary	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
Secondary	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