E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acromegaly is a chronic disorder caused by GH hypersecretion, most commonly as a result of a GH-secreting pituitary adenoma. |
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E.1.1.1 | Medical condition in easily understood language |
Acromegaly is a hormonal disorder that results from too much growth hormone (GH) in the body. In most cases the overproduction of GH is due to a benign tumor of the pituitary gland called an adenoma. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10000599 |
E.1.2 | Term | Acromegaly |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To evaluate the safety and tolerability of ISIS 766720 subcutaneous (SC) injection as a monotherapy in patients with acromegaly.
- To evaluate the efficacy of ISIS 766720 SC injection on serum insulin-like growth factor-1 (IGF-1) as a monotherapy in patients with acromegaly.
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of ISIS 766720 SC to normalize serum IGF-1 levels. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements
2. Males or females with a documented diagnosis of Acromegaly* who are 18 to 75 years old (inclusive) at the time of informed consent
* Defined as a previous diagnosis of GH-secreting adenoma by surgical pathology; or the presence of a pituitary adenoma identified on magnetic resonance imaging (MRI) or computed tomography (CT) Scan (if MRI is contraindicated) and serum IGF-1 levels above the upper limit of normal (ULN) for age and sex at time of diagnosis (serum IGF-1 level and imaging at diagnosis will be collected in the case report forms [CRF])
3.Have had pituitary surgery (e.g. transsphenoidal) unless there was a contraindication to surgery and are either acromegaly medical treatment naïve, or who had not taken any other acromegaly medications prior to the screening visit as outlined below:
bromocriptine: 2 weeks
cabergoline: 4 weeks
quinagolide: 4 weeks
octreotide daily injection (SC) or oral formulation: 4 weeks
pegvisomant: 4 weeks
octreotide LAR: 4 months
pasireotide LAR: 4 months
lanreotide (all formulations): 4 months
4. At Screening, serum IGF-1 (performed at central lab) between 1.3 to 5 × ULN, inclusive, adjusted for age and sex. IGF 1 can be repeated once and averaged to determine eligibility if the initial result is between 1.1-1.3 × ULN, or between 5-5.3 × ULN
5. Females must be non-pregnant and non-lactating, and either:
a. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy)
b. post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative medical cause and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory involved)
c. abstinent or
d. Women of childbearing potential (WOCBP) should agree to taking all precaution to avoid pregnancy during the Trial Period (including post treatment), including agreeing to receive pregnancy testing before each monthly dose, using 1 highly effective method of birth control from the time of signing the informed consent form (ICF) until 14 weeks after the last dose of ISIS 766720 administration
Males must be either:
e. surgically sterile
f. abstinent or
g. if engaged in sexual relations with a female of child-bearing potential, the patient must be using a highly effective contraceptive method from the time of signing the ICF until 14 weeks after the last dose of ISIS 766720
6. Willing to refrain from strenuous exercise/activity (for example heavy lifting, weight training, intense aerobics classes etc.) for at least 24 hours prior to study visits
7. Willing to refrain from alcohol or tobacco use for 8 hours prior to study visits. |
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E.4 | Principal exclusion criteria |
1. Clinically significant abnormalities in medical history or physical examination
2. Patients who received surgery for pituitary adenoma within the last 3 months before the trial, and/or planning to receive surgery during the trial
3. Patients who received radiotherapy for pituitary adenoma within the last 2 years before the trial, and/or planning to receive radiotherapy during the trial
4. Patients with a pituitary tumor that, per Investigator judgment, is worsening (e.g., either growing, or at risk of compressing or abutting the optic chiasm or other vital structures) as assessed by pituitary/sellar MRI protocol at Screening or within 3 months of Screening. CT scan is allowed if MRI is contraindicated.
5. Evidence of decompensated cardiac function per medical judgement and/or New York Heart Association (NYHA) Class 3 or 4
6. Clinical evidence of symptomatic hyperprolactinemia that would necessitate treatment
7. Symptomatic cholelithiasis, and/or choledocholithiasis
8. Have a diagnosis of Gilbert’s Syndrome
9. Patients with history of hypoglycemia unawareness (who have had > 3 severe episodes in the past 6 months) or documented reactive hypoglycemia
10. Screening laboratory results as described in the protocol, or any other CS abnormalities in Screening laboratory values that would render a patient unsuitable for inclusion (abnormalities may be retested for eligibility purposes)
11. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
12. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
13. Active infection with human immunodeficiency virus (HIV), hepatitis C (HCV) or hepatitis B (HBV) diagnosed by initial serology testing and confirmed with RNA testing, or prior treatment for HCV. Patients at Screening who test positive by serology, but negative by RNA may be allowed in consultation with the Sponsor Medical Monitor or Designee
14. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, follicular Stage 1 or papillary thyroid cancer that has been successfully treated; patients that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the Sponsor Medical Monitor or Designee
15. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer
16. Treatment with any non-ION- or ISIS-oligonucleotide (including small interfering ribonucleic acid [siRNA]) at any time or prior treatment with an ION- or ISIS-oligonucleotide within 9 months of Screening. Patients that have previously received only a single-dose of an ION or ISIS-oligonucleotide as part of a clinical study may be included as long as duration ≥ 4 months has elapsed since dosing
17. History of bleeding diathesis or coagulopathy
18. Recent history of, or current drug or alcohol abuse that could affect study compliance per Investigator judgment
19. Patients may not have chronic systemic use of weight loss medications (except GLP-1 agonist or SGLT2 inhibitors) or participate in weight loss programs within 2 months before Screening. Patients taking GLP-1 agonist or SGLT2 inhibitors indicated for weight loss maybe allowed with prior consultation with the Sponsor Medical Monitor or Designee
20. Patients on anti-diabetes medications must be on a stable dose and regimen for ≥ 3 months prior to Screening. Patients taking insulin can be allowed with prior consultation with the Sponsor Medical Monitor or Designee
21. Patients on estrogen containing medications must be on a stable dose and regimen for ≥ 3 months prior to Screening
22.Patients on glucocorticoid replacement used for adrenal insufficiency must be on a stable dose and regimen (increases used to prevent adrenal crisis is permitted) for ≥ 3 months prior to Screening
23.Use of oral anticoagulants, unless the dose has been stable for 4 weeks prior to the first dose of ISIS 766720 and regular clinical monitoring is performed during the trial
24.Blood donation of 50 to 499 mL within 30 days of Screening or of > 499 mL within 60 days of Screening and during the trial
25.Have any other conditions, which, in the opinion of the Investigator and Sponsor would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the Study |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the percent change in IGF-1 from Baseline to Week 27. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Comparison of percent change in IGF-1 from Baseline to Week 27 between ISIS 766720 80 mg, 120 mg and 160 mg groups in the Per Protocol Set. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include:
• Patients who achieve normalized IGF-1 levels to within 1.2 times gender and age limits at Day 183 (Week 27)
• Patients who achieve normalized IGF-1 levels to within 1.0 times gender and age limits at Day 183 (Week 27)
• Change from Baseline in serum IGF-1 over time
• Percent change from Baseline in serum IGF-1 over time |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Patients who achieve normalized IGF-1 levels to within 1.2 times gender and age limits: at Day 183 (Week 27)
• Patients who achieve normalized IGF-1 levels to within 1.0 times gender and age limits: at Day 183 (Week 27)
• Serum IGF-1 level change measured throughout the study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Russian Federation |
Serbia |
United States |
Estonia |
Hungary |
Italy |
Latvia |
Lithuania |
Poland |
Romania |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |