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Clinical Trial Results:
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)

Summary
EudraCT number	2017-004259-22
Trial protocol	HU AT LT CZ PL RO
Global end of trial date	02 Apr 2021

Results information
Results version number	v1(current)
This version publication date	15 Dec 2022
First version publication date	15 Dec 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ISIS 766720-CS2

ISRCTN number

US NCT number

NCT03548415

WHO universal trial number (UTN)

Sponsor organisation name

Ionis Pharmaceuticals, Inc

Sponsor organisation address

2855 Gazelle Court, Carlsbad, United States, 92010

Public contact

Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc., +1 760603-3804, ClinicalTrials@ionisph.com

Scientific contact

Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc., +1 760603-3804, ClinicalTrials@ionisph.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Apr 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Apr 2021

Was the trial ended prematurely?

Main objective of the trial

- To evaluate the efficacy of ISIS 766720 subcutaneous (SC) injection on serum insulin-like growth factor 1 (IGF-1) vs. placebo as an add-on therapy to long acting somatostatin receptor ligands (SRL) octreotide or lanreotide. - To evaluate the safety and tolerability of ISIS 766720 SC injection vs. placebo on add-on therapy of SRL.

Protection of trial subjects

Each subject, or legally acceptable representative, signed an informed consent form before participating in the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Sep 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Russian Federation: 17

Country: Number of subjects enrolled

United States: 7

Country: Number of subjects enrolled

Serbia: 2

Country: Number of subjects enrolled

Poland: 4

Country: Number of subjects enrolled

Romania: 1

Country: Number of subjects enrolled

Hungary: 3

Country: Number of subjects enrolled

Lithuania: 9

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Adult subjects diagnosed with acromegaly 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.

Screening details

Subjects were randomized into 4 cohorts [A and B in 2:1 ratio; 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.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects received placebo by subcutaneous injection (SC) once every 4 weeks for 16 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

IONIS GHR-LRx-matching placebo administered subcutaneously.

Cohort A: IONIS GHR-LRx, 60 mg

Arm description

Subjects received IONIS GHR-LRx, 60 milligrams (mg), SC, once every 4 weeks for 16 weeks.

Arm type

Experimental

Investigational medicinal product name

IONIS-GHR-LRx

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

IONIS GHR-LRx, 60 mg, administered subcutaneously.

Cohort B: IONIS GHR-LRx, 80 mg

Arm description

Subjects received IONIS GHR-LRx, 80 mg, SC, once every 4 weeks for 16 weeks.

Arm type

Experimental

Investigational medicinal product name

IONIS-GHR-LRx

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

IONIS GHR-LRx, 80 mg, administered subcutaneously.

Cohort C: IONIS GHR-LRx, 120 mg

Arm description

Subjects received IONIS GHR-LRx, 120 mg, SC, once every 4 weeks for 16 weeks.

Arm type

Experimental

Investigational medicinal product name

IONIS-GHR-LRx

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

IONIS GHR-LRx, 120 mg, administered subcutaneously.

Cohort D: IONIS GHR-LRx, 160 mg

Arm description

Subjects received IONIS GHR-LRx, 160 mg, SC, once every 4 weeks for 16 weeks.

Arm type

Experimental

Investigational medicinal product name

IONIS-GHR-LRx

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

IONIS GHR-LRx, 160 mg, administered subcutaneously.

Number of subjects in period 1	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
Started	12	12	11	2	6
Per-Protocol Set	12	11	11	2	5
Completed	12	11	11	2	5
Not completed	0	1	0	0	1
Adverse Event or Serious Adverse Event	-	1	-	-	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Subjects received placebo by subcutaneous injection (SC) once every 4 weeks for 16 weeks.

Reporting group title

Cohort A: IONIS GHR-LRx, 60 mg

Reporting group description

Subjects received IONIS GHR-LRx, 60 milligrams (mg), SC, once every 4 weeks for 16 weeks.

Reporting group title

Cohort B: IONIS GHR-LRx, 80 mg

Reporting group description

Subjects received IONIS GHR-LRx, 80 mg, SC, once every 4 weeks for 16 weeks.

Reporting group title

Cohort C: IONIS GHR-LRx, 120 mg

Reporting group description

Subjects received IONIS GHR-LRx, 120 mg, SC, once every 4 weeks for 16 weeks.

Reporting group title

Cohort D: IONIS GHR-LRx, 160 mg

Reporting group description

Subjects received IONIS GHR-LRx, 160 mg, SC, once every 4 weeks for 16 weeks.

Reporting group values	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
Number of subjects	12	12	11	2	6	43
Age categorical
Units: Subjects
Adults (18-64 years)						0
From 65-84 years						0
Age continuous
The Safety Set included all subjects who were randomized and received at least one dose of Study Drug.
Units: years
arithmetic mean (standard deviation)	45.3 ± 11.7	48.9 ± 13.6	52.1 ± 14.9	53.5 ± 2.1	46.0 ± 13.3	-
Gender categorical
The Safety Set included all subjects who were randomized and received at least one dose of Study Drug.
Units: Subjects
Female	8	9	6	0	4	27
Male	4	3	5	2	2	16
Ethnicity (NIH/OMB)
The Safety Set included all subjects who were randomized and received at least one dose of Study Drug.
Units: Subjects
Hispanic or Latino	0	0	0	0	0	0
Not Hispanic or Latino	12	12	11	2	6	43
Unknown or Not Reported	0	0	0	0	0	0
Race (NIH/OMB)
The Safety Set included all subjects who were randomized and received at least one dose of Study Drug.
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0
Asian	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	0	0	0	0	1	1
White	12	12	11	2	5	42
More than one race	0	0	0	0	0	0

End points

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Reporting group title

Placebo

Reporting group description

Subjects received placebo by subcutaneous injection (SC) once every 4 weeks for 16 weeks.

Reporting group title

Cohort A: IONIS GHR-LRx, 60 mg

Reporting group description

Subjects received IONIS GHR-LRx, 60 milligrams (mg), SC, once every 4 weeks for 16 weeks.

Reporting group title

Cohort B: IONIS GHR-LRx, 80 mg

Reporting group description

Subjects received IONIS GHR-LRx, 80 mg, SC, once every 4 weeks for 16 weeks.

Reporting group title

Cohort C: IONIS GHR-LRx, 120 mg

Reporting group description

Subjects received IONIS GHR-LRx, 120 mg, SC, once every 4 weeks for 16 weeks.

Reporting group title

Cohort D: IONIS GHR-LRx, 160 mg

Reporting group description

Subjects received IONIS GHR-LRx, 160 mg, SC, once every 4 weeks for 16 weeks.

Subject analysis set title

Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Per-protocol Set included all randomized subjects who received at least one dose of Study Drug and had at least one post-baseline efficacy or pharmacodynamic assessment, received at least 5 of the 6 doses of Study Drug with the first 3 doses administered on schedule, and had no significant protocol deviations that would have been expected to affect efficacy.

Subject analysis set title

ISIS 766720 Low Dose

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received IONIS GHR-LRx, 60 or 80 mg, SC, once every 4 weeks for 16 weeks.

Subject analysis set title

ISIS 766720 High Dose

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received IONIS GHR-LRx, 120 or 160 mg, SC, once every 4 weeks for 16 weeks.

Primary: Percent Change in Serum Insulin-like Growth Factor-1 (IGF-1) From Baseline to 28 Days After Last Dose

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End point title

Percent Change in Serum Insulin-like Growth Factor-1 (IGF-1) From Baseline to 28 Days After Last Dose

End point description

IGF-1 is a hormone that manages 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 last non-missing value prior to first administration of Study Drug (ISIS 766720 or placebo). Negative % change from Baseline indicated improvement. To perform a meaningful assessment of pharmacodynamic (PD) activity of ISIS 766720, lower dose groups (60 mg and 80 mg) and higher dose groups (120mg &160mg) 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. Per-protocol Set included all randomised subjects who received at least one dose of Study Drug and had at least one post-baseline efficacy or PD assessment, received at least 5 of the 6 doses of Study Drug with first 3 doses administered on schedule, and had no significant protocol deviations that would have been expected to affect efficacy. Low dose=60/80 mg, high=120/160 mg.

End point type

Primary

End point timeframe

Baseline and 28 days after last dose (Day 141)

End point values	Placebo	ISIS 766720 Low Dose	ISIS 766720 High Dose
Number of subjects analysed	12	22	7
Units: percent change
arithmetic mean (standard deviation)	8.9 ± 31.5	-2.8 ± 33.1	-7.5 ± 16.3

Statistical Analysis 1

Comparison groups

Placebo v ISIS 766720 Low Dose

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.306

Method

Van Elteren test

Confidence interval

Primary: Number of Subjects With TEAEs Related to Clinically Significant Vital Sign Findings

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End point title

Number of Subjects With TEAEs Related to Clinically Significant Vital Sign Findings ^[1]

End point description

Vitals signs included blood pressure, heart rate, respiratory rate, and temperature recorded throughout the study. Clinical significance was determined by the investigator. The Safety Set included all subjects who were randomized and received at least one dose of Study Drug.

End point type

Primary

End point timeframe

Up to 211 days

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Inferential statistical analyses was not performed for the safety endpoints. Descriptive statistics are included (number of subjects).

End point values	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
Number of subjects analysed	12	12	11	2	6
Units: subjects
Hypotension	0	1	0	0	0
Hypertension	0	0	1	0	0

No statistical analyses for this end point

Primary: Number of Subjects With TEAEs Related to Clinically Significant Physical Examination Findings

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End point title

Number of Subjects With TEAEs Related to Clinically Significant Physical Examination Findings ^[2]

End point description

Physical examination included weight and body mass index (BMI) recorded throughout the study. Clinical significance was determined by the investigator. The Safety Set included all subjects who were randomized and received at least one dose of Study Drug.

End point type

Primary

End point timeframe

Up to 211 days

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Inferential statistical analyses was not performed for the safety endpoints. Descriptive statistics are included (number of subjects).

End point values	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
Number of subjects analysed	12	12	11	2	6
Units: subjects	0	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects With TEAEs Related to Clinically Significant Laboratory Evaluation Findings

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End point title

Number of Subjects With TEAEs Related to Clinically Significant Laboratory Evaluation Findings ^[3]

End point description

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. The Safety Set included all subjects who were randomized and received at least one dose of Study Drug.

End point type

Primary

End point timeframe

Up to 211 days

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Inferential statistical analyses was not performed for the safety endpoints. Descriptive statistics are included (number of subjects).

End point values	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
Number of subjects analysed	12	12	11	2	6
Units: subjects
Blood urine present	0	0	0	1	0
Mean cell volume increased	0	1	0	0	0
Urine protein/creatinine ratio increased	0	0	1	0	0
Hyperglycaemia	1	0	0	1	0

No statistical analyses for this end point

Primary: Number of Subjects With TEAEs Related to Clinically Significant Electrocardiogram (ECG) Findings

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End point title

Number of Subjects With TEAEs Related to Clinically Significant Electrocardiogram (ECG) Findings ^[4]

End point description

ECG assessments included QT, QRS duration, PR interval, ventricular rate, QTcB, QTcF. The Safety Set included all subjects who were randomized and received at least one dose of Study Drug.

End point type

Primary

End point timeframe

Up to 211 days

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Inferential statistical analyses was not performed for the safety endpoints. Descriptive statistics are included (number of subjects).

End point values	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
Number of subjects analysed	12	12	11	2	6
Units: subjects	2	2	1	1	0

No statistical analyses for this end point

Primary: Number of Subjects Who Required Concomitant Medications

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End point title

Number of Subjects Who Required Concomitant Medications ^[5]

End point description

Number of subjects who used medication other than the study drug were reported. The Safety Set included all subjects who were randomized and received at least one dose of Study Drug.

End point type

Primary

End point timeframe

Up to 211 days

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Inferential statistical analyses was not performed for the safety endpoints. Descriptive statistics are included (number of subjects).

End point values	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
Number of subjects analysed	12	12	11	2	6
Units: subjects	12	12	11	2	6

No statistical analyses for this end point

Secondary: Number of Subjects Achieving Normalized IGF-1 Levels to Within 1.2 Times of Gender and Age Limits at 28 Days After Last Dose

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End point title

Number of Subjects Achieving Normalized IGF-1 Levels to Within 1.2 Times of Gender and Age Limits at 28 Days After Last Dose

End point description

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. Per-protocol Set. Low dose refers to 60 mg or 80 mg, High dose refers to 120 mg or 160 mg.

End point type

Secondary

End point timeframe

Baseline to 28 days after last dose (Day 141)

End point values	Placebo	ISIS 766720 Low Dose	ISIS 766720 High Dose
Number of subjects analysed	12	22	7
Units: subjects	0	5	1

No statistical analyses for this end point

Secondary: Number of Subjects Achieving Normalized IGF-1 Levels to Within 1.0 Times of Gender and Age Limits at 28 Days After Last Dose

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End point title

Number of Subjects Achieving Normalized IGF-1 Levels to Within 1.0 Times of Gender and Age Limits at 28 Days After Last Dose

End point description

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. Per-protocol Set. Low dose refers to 60 mg or 80 mg, High dose refers to 120 mg or 160 mg.

End point type

Secondary

End point timeframe

Baseline to 28 days after last dose (Day 141)

End point values	Placebo	ISIS 766720 Low Dose	ISIS 766720 High Dose
Number of subjects analysed	12	22	7
Units: subjects	0	2	0

No statistical analyses for this end point

Secondary: Change From Baseline in Serum IGF-1 Over Time

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End point title

Change From Baseline in Serum IGF-1 Over Time

End point description

IGF-1 is a hormone that manages effects of GH in 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 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. Per-protocol Set. Number analyzed is the number of subjects with data available at specific timepoints. Low dose refers to 60 mg or 80 mg, High dose refers to 120 mg or 160 mg.

End point type

Secondary

End point timeframe

Baseline, Days 15, 29, 43, 57, 71, 85, 99, 112, 127, 141, 155, 183, and 211

End point values	Placebo	ISIS 766720 Low Dose	ISIS 766720 High Dose
Number of subjects analysed	12	22	7
Units: nanograms per milliliter (ng/mL)
arithmetic mean (standard deviation)
Baseline (n=12, 22, 7)	386 ± 154	422 ± 214	419 ± 143
CFB at Day 15 (n=12, 22, 7)	33 ± 112	-46 ± 108	-10 ± 47
CFB at Day 29 (n=12, 22, 7)	23 ± 71	-30 ± 140	-68 ± 55
CFB at Day 43 (n=12, 21, 7)	17 ± 114	-41 ± 142	-88 ± 95
CFB at Day 57 (n=12, 22, 7)	52 ± 120	-39 ± 147	-74 ± 63
CFB at Day 71 (n=12, 22, 7)	9 ± 115	-71 ± 163	-78 ± 76
CFB at Day 85 (n=12, 22, 7)	9 ± 91	-55 ± 136	-90 ± 14
CFB at Day 99 (n=12, 22, 7)	13 ± 124	-49 ± 104	-104 ± 78
CFB at Day 112 (n=12, 22, 7)	31 ± 93	-36 ± 100	-61 ± 70
CFB at Day 127 (n=12, 21, 7)	19 ± 83	-48 ± 133	-74 ± 69
CFB at Day 141 (n=12, 22, 7)	20 ± 100	-39 ± 140	-48 ± 92
CFB at Day 155 (n=8, 20, 3)	1 ± 91	-47 ± 144	-98 ± 112
CFB at Day 183 (n=8, 18, 3)	-13 ± 87	-45 ± 155	-15 ± 146
CFB at Day 211 (n=8, 17, 2)	13 ± 116	-55 ± 161	-92 ± 97

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Serum IGF-1 Over Time

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End point title

Percent Change From Baseline in Serum IGF-1 Over Time

End point description

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. Per-protocol Set. Low dose refers to 60 mg or 80 mg, High dose refers to 120mg or 160mg.

End point type

Secondary

End point timeframe

Baseline, Days 15, 29, 43, 57, 71, 85, 99, 112, 127, 155, 183, and 211

End point values	Placebo	ISIS 766720 Low Dose	ISIS 766720 High Dose
Number of subjects analysed	12	22	7
Units: percent change
arithmetic mean (standard deviation)
Baseline (n=12, 22, 7)	386 ± 154	422 ± 214	419 ± 143
Percent CFB at Day 15 (n=12, 22, 7)	11.2 ± 31.3	-6.0 ± 24.5	-0.2 ± 11.9
Percent CFB at Day 29 (n=12, 22, 7)	9.3 ± 26.2	-3.5 ± 30.0	-14.8 ± 6.8
Percent CFB at Day 43 (n=12, 21, 7)	9.6 ± 35.7	-41 ± 28.4	-18.3 ± 18.5
Percent CFB at Day 57 (n=12, 22, 7)	14.3 ± 34.5	-3.4 ± 31.9	-16.6 ± 11.6
Percent CFB at Day 71 (n=12, 22, 7)	8.8 ± 33.4	-9.0 ± 42.0	-16.5 ± 12.3
Percent CFB at Day 85 (n=12, 22, 7)	4.2 ± 27.2	-5.6 ± 32.5	-16.7 ± 19.4
Percent CFB at Day 99 (n=12, 22, 7)	6.6 ± 38.8	-7.1 ± 30.1	-25.1 ± 18.0
Percent CFB at Day 112 (n=12, 22, 7)	12.1 ± 29.8	-4.0 ± 33.6	-12.3 ± 9.3
Percent CFB at Day 127 (n=12, 21, 7)	6.3 ± 19.6	-4.7 ± 30.2	-16.0 ± 9.0
Percent CFB at Day 141 (n=12, 22, 7)	8.9 ± 31.5	-2.8 ± 33.1	-7.5 ± 16.3
Percent CFB at Day 155 (n=8, 20, 3)	4.1 ± 26.0	-3.5 ± 32.0	-18.1 ± 14.1
Percent CFB at Day 183 (n=8, 18, 3)	0.1 ± 26.2	-2.5 ± 38.7	1.6 ± 25.9
Percent CFB at Day 211 (n=8, 17, 2)	2.2 ± 30.6	-8.2 ± 32.7	-15.6 ± 10.5

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 211 days

Adverse event reporting additional description

The Safety Set included all subjects who were randomized and received at least one dose of Study Drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Placebo

Reporting group description

Subjects received placebo by subcutaneous injection (SC) once every 4 weeks for 16 weeks.

Reporting group title

Cohort A: IONIS GHR-LRx, 60 mg

Reporting group description

Subjects received IONIS GHR-LRx, 60 milligrams (mg), SC, once every 4 weeks for 16 weeks.

Reporting group title

Cohort B: IONIS GHR-LRx, 80 mg

Reporting group description

Subjects received IONIS GHR-LRx, 80 mg, SC, once every 4 weeks for 16 weeks.

Reporting group title

Cohort C: IONIS GHR-LRx, 120 mg

Reporting group description

Subjects received IONIS GHR-LRx, 120 mg, SC, once every 4 weeks for 16 weeks.

Reporting group title

Cohort D: IONIS GHR-LRx, 160 mg

Reporting group description

Subjects received IONIS GHR-LRx, 160 mg, SC, once every 4 weeks for 16 weeks.

Serious adverse events	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 subjects affected by serious adverse events
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 6 (16.67%)
number of deaths (all causes)	0	1	0	0	0
number of deaths resulting from adverse events	0	1	0	0	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Intra-abdominal haemorrhage
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastrointestinal bacterial infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	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 subjects affected by non serious adverse events
subjects affected / exposed	8 / 12 (66.67%)	11 / 12 (91.67%)	7 / 11 (63.64%)	2 / 2 (100.00%)	5 / 6 (83.33%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningioma
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Renal cancer stage I
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Vascular disorders
Hot flush
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Hypertension
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Hypotension
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Poor peripheral circulation
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Thrombophlebitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Chest pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	1
Chills
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Fatigue
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	1	0	0
Injection site erythema
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	5	0	0
Injection site inflammation
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Pain
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Pyrexia
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Epistaxis
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Nasal congestion
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Snoring
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Upper respiratory tract inflammation
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Bacterial test positive
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	0	0	1
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 12 (8.33%)	1 / 12 (8.33%)	2 / 11 (18.18%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	2	0	1
Blood urine present
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0
Electrocardiogram QRS complex prolonged
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Heart rate irregular
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Mean cell volume increased
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Urine protein/creatinine ratio increased
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Fall
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Limb injury
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Meniscus injury
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Muscle strain
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Wound
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Congenital, familial and genetic disorders
Type V hyperlipidaemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Bradycardia
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Bundle branch block
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Coronary artery disease
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Left ventricular hypertrophy
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0
Myocardial infarction
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Palpitations
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Sinus bradycardia
subjects affected / exposed	0 / 12 (0.00%)	2 / 12 (16.67%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0	0
Supraventricular extrasystoles
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Headache
subjects affected / exposed	1 / 12 (8.33%)	1 / 12 (8.33%)	2 / 11 (18.18%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	9	0	1
Hypoaesthesia
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Paraesthesia
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Somnolence
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	2 / 12 (16.67%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0	0
Thrombocytopenia
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Eye disorders
Asthenopia
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	2 / 11 (18.18%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	2	0	0
Abdominal pain upper
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Constipation
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	1 / 11 (9.09%)	1 / 2 (50.00%)	0 / 6 (0.00%)
occurrences all number	1	0	3	1	0
Diarrhoea
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	1 / 11 (9.09%)	1 / 2 (50.00%)	1 / 6 (16.67%)
occurrences all number	0	3	1	1	1
Frequent bowel movements
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Gastritis
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Glossitis
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Intra-abdominal haemorrhage
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Nausea
subjects affected / exposed	1 / 12 (8.33%)	2 / 12 (16.67%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	2	2	1	0	2
Pancreatitis
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Pancreatitis acute
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Vomiting
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Cholelithiasis
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	0	0	1
Renal and urinary disorders
Albuminuria
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Bladder pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0
Dysuria
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Haematuria
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Nephrolithiasis
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0	0
Renal cyst
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Endocrine disorders
Acromegaly
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	1
Muscle spasms
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 11 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0
Myalgia
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Infections and infestations
Cervicitis
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Enterovirus infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Gastrointestinal bacterial infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Nasopharyngitis
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)
occurrences all number	2	0	0	0	1
Periodontitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Pharyngitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Pneumonia
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Pyelonephritis chronic
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0
Respiratory tract infection
subjects affected / exposed	0 / 12 (0.00%)	2 / 12 (16.67%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0	0
Septic shock
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 12 (0.00%)	2 / 12 (16.67%)	1 / 11 (9.09%)	0 / 2 (0.00%)	2 / 6 (33.33%)
occurrences all number	0	2	1	0	3
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Glucose tolerance impaired
subjects affected / exposed	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0
Hyperglycaemia
subjects affected / exposed	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 11 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	1	0
Hyperkalaemia
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0
Hypoglycaemia
subjects affected / exposed	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0

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Were there any global substantial amendments to the protocol? Yes

22 Jun 2018

Amendment 1 clarified inconsistencies within the protocol and included flexibility with protocol procedures to improve operational logistics at the study centers and included recommendations from the Food and Drug Administration (FDA).

10 Aug 2018

Amendment 2 updated the inclusion criteria pertaining to the use of contraceptive methods for Women of Child Bearing Potential (WOCBP) and men who were engaged in sexual relations with WOCBP so that the requirements corresponded to the latest International Council for Harmonisation (ICH) Clinical Trial Facilitation Group (CTFG) recommendations dated 15 September 2014. Reference to pituitary tumor in the section on Study Drug discontinuation was revised to be consistent with exclusion criterion #4.

14 May 2019

Amendment 3 added Cohort C (120 mg) to explore the safety and efficacy of a higher dose to facilitate Phase 3 dose selection. Since the protocol was powered for 30 subjects , it was planned that recruitment for Cohorts A and B would be stopped at or about 30 subjects and Cohort C initiated. The amendment included the potential to enroll Cohort D (160 mg) but data from the lower dose cohorts would be reviewed prior to initiation of that cohort. The amendment also incorporated clarifications that had been provided in “Memos to Investigators.” Addendum 1 to Amendment 3 (17 July 2020) formalized guidance given in the 1 May 2020 memo “ISIS 766720-CS2: Coronavirus COVID-19 Guidance” to Investigators. The addendum allowed for additional visits and procedures to be conducted via home health visits when in-clinic visits were affected due to local precautions and restrictions related to the COVID-19 pandemic that may have limited the subject's ability to go to the clinic.

18 May 2020

Amendment 4 updated several requirements for patient eligibility for the study based on available safety data, formalized the procedures added to the protocol based on the guidance given in the 1 May 2020 Memo to Investigators, and updated the protocol to reflect the decision to conduct Cohort D.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Not specified

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent Change in Serum Insulin-like Growth Factor-1 (IGF-1) From Baseline to 28 Days After Last Dose

Primary: Percent Change in Serum Insulin-like Growth Factor-1 (IGF-1) From Baseline to 28 Days After Last Dose

Primary: Number of Subjects With TEAEs Related to Clinically Significant Vital Sign Findings

Primary: Number of Subjects With TEAEs Related to Clinically Significant Vital Sign Findings

Primary: Number of Subjects With TEAEs Related to Clinically Significant Physical Examination Findings

Primary: Number of Subjects With TEAEs Related to Clinically Significant Physical Examination Findings

Primary: Number of Subjects With TEAEs Related to Clinically Significant Laboratory Evaluation Findings

Primary: Number of Subjects With TEAEs Related to Clinically Significant Laboratory Evaluation Findings

Primary: Number of Subjects With TEAEs Related to Clinically Significant Electrocardiogram (ECG) Findings

Primary: Number of Subjects With TEAEs Related to Clinically Significant Electrocardiogram (ECG) Findings

Primary: Number of Subjects Who Required Concomitant Medications

Primary: Number of Subjects Who Required Concomitant Medications

Secondary: Number of Subjects Achieving Normalized IGF-1 Levels to Within 1.2 Times of Gender and Age Limits at 28 Days After Last Dose

Secondary: Number of Subjects Achieving Normalized IGF-1 Levels to Within 1.2 Times of Gender and Age Limits at 28 Days After Last Dose

Secondary: Number of Subjects Achieving Normalized IGF-1 Levels to Within 1.0 Times of Gender and Age Limits at 28 Days After Last Dose

Secondary: Number of Subjects Achieving Normalized IGF-1 Levels to Within 1.0 Times of Gender and Age Limits at 28 Days After Last Dose

Secondary: Change From Baseline in Serum IGF-1 Over Time

Secondary: Change From Baseline in Serum IGF-1 Over Time

Secondary: Percent Change From Baseline in Serum IGF-1 Over Time

Secondary: Percent Change From Baseline in Serum IGF-1 Over Time

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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