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)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03548415

Enrollment

Registered

2018-06-07

Start date

2018-09-13

Completion date

2021-04-02

Last updated

2022-11-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Acromegaly

Keywords

Acromegaly, IONIS-GHR-LRx

Brief 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.

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).

Interventions

DRUGIONIS-GHR-LRx

IONIS GHR-LRx administered subcutaneously.

DRUGPlacebo

Placebo administered subcutaneously.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With TEAEs Related to Clinically Significant Electrocardiogram (ECG) Findings	Up to 211 days	ECG assessments included QT, QRS duration, PR interval, ventricular rate, QTcB, QTcF.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Up to 211 days	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.
Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings	Up to 211 days	Vitals signs included blood pressure, heart rate, respiratory rate, and temperature recorded throughout the study. Clinical significance was determined by the investigator.
Number of Participants With TEAEs Related to Clinically Significant Physical Examination Findings	Up to 211 days	Physical examination included weight and body mass index (BMI) recorded throughout the study. Clinical significance was determined by the investigator.
Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings	Up to 211 days	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.
Percent Change in Serum Insulin-like Growth Factor-1 (IGF-1) From Baseline to 28 Days After Last Dose	Baseline and 28 days after last dose (Day 141)	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.

Secondary

Measure	Time frame	Description
Number of Participants Achieving Normalized IGF-1 Levels to Within 1.0 Times of Gender and Age Limits at 28 Days After Last Dose	Baseline to 28 days after last dose (Day 141)	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.
Change From Baseline in Serum IGF-1 Over Time	Baseline, Days 15, 29, 43, 57, 71, 85, 99, 112, 127, 141, 155, 183, and 211	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.
Percent Change From Baseline in Serum IGF-1 Over Time	Baseline, Days 15, 29, 43, 57, 71, 85, 99, 112, 127, 155, 183, and 211	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.
Number of Participants Achieving Normalized IGF-1 Levels to Within 1.2 Times of Gender and Age Limits at 28 Days After Last Dose	Baseline to 28 days after last dose (Day 141)	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.

Countries

Hungary, Lithuania, Poland, Romania, Russia, Serbia, United States

Participant flow

Recruitment details

Participants took part in the study at 24 investigative sites in Lithuania, Hungary, the United States of America, Serbia, Russia, Poland, and Romania from 13 September 2018 to 02 April 2021.

Pre-assignment details

Adult participants diagnosed with acromegaly were randomized into 4 cohorts \[Cohorts A and B in 2:1 ratio; Cohorts C and D in 5:1 ratio\] to receive IONIS GHR-LRx or placebo. Due to enrollment difficulties associated with (COVID-19) pandemic, treatment groups IONIS GHR-LRx, 120 mg and IONIS GHR-LRx, 160 mg did not complete enrollment resulting in cohort sizes smaller than planned.

Participants by arm

Arm	Count
Placebo Participants received placebo by subcutaneous injection (SC) once every 4 weeks for 16 weeks.	12
Cohort A: IONIS GHR-LRx, 60 mg Participants received IONIS GHR-LRx, 60 milligrams (mg), SC, once every 4 weeks for 16 weeks.	12
Cohort B: IONIS GHR-LRx, 80 mg Participants received IONIS GHR-LRx, 80 mg, SC, once every 4 weeks for 16 weeks.	11
Cohort C: IONIS GHR-LRx, 120 mg Participants received IONIS GHR-LRx, 120 mg, SC, once every 4 weeks for 16 weeks.	2
Cohort D: IONIS GHR-LRx, 160 mg Participants received IONIS GHR-LRx, 160 mg, SC, once every 4 weeks for 16 weeks.	6
Total	43

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Adverse Event or Serious Adverse Event	0	1	0	0	1

Baseline characteristics

Characteristic	Placebo	Cohort A: IONIS GHR-LRx, 60 mg	Cohort B: IONIS GHR-LRx, 80 mg	Cohort C: IONIS GHR-LRx, 120 mg	Cohort D: IONIS GHR-LRx, 160 mg	Total
Age, Continuous	45.3 years STANDARD_DEVIATION 11.7	48.9 years STANDARD_DEVIATION 13.6	52.1 years STANDARD_DEVIATION 14.9	53.5 years STANDARD_DEVIATION 2.1	46.0 years STANDARD_DEVIATION 13.3	48.5 years STANDARD_DEVIATION 12.9
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	12 Participants	12 Participants	11 Participants	2 Participants	6 Participants	43 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	00 Participants	1 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	12 Participants	12 Participants	11 Participants	2 Participants	5 Participants	42 Participants
Sex: Female, Male Female	8 Participants	9 Participants	6 Participants	0 Participants	4 Participants	27 Participants
Sex: Female, Male Male	4 Participants	3 Participants	5 Participants	2 Participants	2 Participants	16 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 12	1 / 12	0 / 11	0 / 2	0 / 6
other Total, other adverse events	8 / 12	11 / 12	7 / 11	2 / 2	5 / 6
serious Total, serious adverse events	0 / 12	1 / 12	1 / 11	0 / 2	1 / 6

Outcome results

Primary