| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| 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 |
Primary objective:
- To evaluate the efficacy of pasireotide LAR in patients with acromegaly who are inadequately controlled with maximal approved doses of currently available somatostatin analogues
Supporting Analysis for Primary objective:
- To assess the proportion of patients achieving GH <1µg/L and IGF-1 <ULN by GH level.
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| E.2.2 | Secondary objectives of the trial |
Core phase:
-assess the changes in mean GH and standardized IGF-1
-assess the proportion of patients achieving GH <1 µg/L and IGF-1 <ULN and by GH level
-assess the proportion of patients achieving GH <1µg/L or IGF-1 levels <ULN and by GH level
-evaluate the tolerability and safety profile of pasireotide LAR
-evaluate the effect of pasireotide LAR on HRQoL
Extension phase:
-assess the proportion of patients achieving IGF-1 <ULN
-assess the proportion of patients achieving GH <1μg/L and IGF-1 <ULN by treatment with pasireotide LAR alone or with
concomitant medications used to treat acromegaly
-assess the proportion of patients achieving GH <1 μg/L by treatment with pasireotide LAR alone or with concomitant
medications used to treat acromegaly
-evaluate the long term tolerability and safety profile of pasireotide LAR
-evaluate the long term effect of pasireotide LAR on HRQoL
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Written informed consent must be obtained prior to any screening procedures
2. Male and female patients ≥ 18 years of age
3. Patients with confirmed diagnosis of inadequately controlled acromegaly as evidenced by the following:
• A mean GH concentration of a 5-point profile over a 2-hour period ≥ 1 µg/L and sex- and age-adjusted IGF-1 >1.3 x ULN
4. Patients treated with high dose of octreotide LAR (30 mg or 40 mg) or lanreotide ATG (120 mg) given as monotherapy for at least 3 months prior to screening (Visit 1)
• Note: Patients currently being treated with octreotide LAR 30 mg from countries where the octreotide LAR 40 mg dose is approved at the time of screening will start a run- in phase in which they will receive the 3 injections of octreotide LAR 40 mg before being evaluated for eligibility for the core phase of the study
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| E.4 | Principal exclusion criteria |
1. Concomitant treatment with other medications known to reduce GH and or IGF-1, other than octreotide LAR or lanreotide ATG, unless discontinued 3 months prior to visit 1 (screening)
2. Patients with compression of the optic chiasm causing any visual field defect that requires surgical intervention
3. Diabetic patients with poor glycaemic control as evidenced by HbA1c >8% at Visit 1 for Group 2 and at both Visit 1 and Visit 5 for Group 1
4. Patients who are hypothyroid and not on adequate replacement therapy
5. Patients with symptomatic cholelithiasis and acute or chronic pancreatitis
6. Patients with clinically significant valvular disease
7. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF >450 ms in males, and >460 ms in females
8. Hypokalaemia, hypomagnesaemia, uncontrolled hypothyroidism, family history of long QT syndrome or concomitant medications with known risk of Torsades de pointes (TdP). Drugs with posible risk of TdP should be avoided whenever feasible.
9. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, history of acute MI less than one year prior to study entry or clinically significant impairment in cardiovascular function
10. Concomitant disease(s) that could prolong the QT interval such as autonomic neuropathy (caused by diabetes or Parkinson’s disease), HIV, cirrhosis, uncontrolled hypothyroidism or cardiac failure
11. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with ALT/AST > 2.0 X ULN, serum bilirubin >2.0 X ULN
12. Presence of Hepatitis B surface antigen (HbsAg) or Hepatitis C antibody test (anti-HCV)
13. Patients with serum creatinine >2.0 X ULN
14. Patients with WBC <3 X 109/L; Hb 90% < LLN; PLT <100 X 109/L
15. Patients with the presence of active or suspected acute or chronic uncontrolled infection
16. Patients who have undergone major surgery/surgical therapy for any cause within 4 weeks prior to visit 1 (screening)
17. Patients with active malignant disease within the last five years (with the exception of basal cell carcinoma or carcinoma in situ of the cervix)
18. Patients with abnormal coagulation (PT and/or APTT elevated by 30% above normal limits) or patients receiving anticoagulants that affect PT (prothrombin time) or APTT (activated partial thromboplastin time)
19. History of syncope or family history of idiopathic sudden death
20. History of immunocompromise, including a positive HIV test result (ELISA and Western blot). A HIV test will not be required; however, previous medical history will be reviewed
21. Known hypersensitivity to somatostatin analogues or any other component of the pasireotide LAR
22. Patients who have a history of alcohol or drug abuse in the 6 month period prior to receiving pasireotide
23. Patients who have given a blood donation (of 400 ml or more) within 2 months before receiving pasireotide
24. Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to dosing
25. Patients with any current or prior medical condition that, in the judgment of the investigator may interfere with the conduct of the study or the evaluation of the study results
26. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study
27. Sexually active males unless they use a condom during intercourse while taking drug and for 3 months following last dose of pasireotide and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
28. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
29. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and 3 months following last dose of pasireotide.
Women are considered post-menopausal and not of child bearing potential if they have had 12
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy
(with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of
oophorectomy alone, only when the reproductive status of the woman has been confirmed by
follow up hormone level assessment is she considered not of child bearing potential.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Proportion of patients who achieved GH <1μg/L and IGF-1 <ULN .
- Proportion of patients who achieved GH <1μg/L and IGF-1 <ULN in patients having GH level at screening between 1 μg/L and 2.5 μg/L, and in patients having GH level at screening >2.5 μg/L |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- at week 36.
- at week 36
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| E.5.2 | Secondary end point(s) |
- Changes in mean GH and standardized IGF-1 .
- Proportion of patients who achieved GH <1µg/L and IGF-1 <ULN and by GH level .
- Proportion of patients who achieved GH <1µg/L or IGF-1 <ULN and by GH level .
- Toxicity will be assessed using the National Cancer Institute-Common Toxicology Criteria Adverse Events version 4 (NCI-CTCAE v.4.03) and for laboratory assessments that include biochemistry, hematology, urinalysis; special safety assessments that include the regular monitoring and recording of blood glucose, insulin, HbA1c, GH and IGF-1, thyroid and liver function tests, gallbladder examinations and ECGs. Concomitant medications/Significant nondrug therapies will be assessed .
- Change in scores as measured by AcroQoL, EQ-5D-5L
For extension phase:
- Proportion of patients who achieved IGF-1 <ULN
- Proportion of patients who achieved GH <1 µg/L and IGF-1 <ULN by treatment with pasireotide LAR alone or with concomitant medications used to treat acromegaly
- Proportion of patients who achieved GH <1 µg/L by treatment with pasireotide LAR alone or with concomitant medications used to treat acromegaly
- Toxicity will be assessed using the National Cancer Institute-Common Toxicology Criteria Adverse Events version 4 (NCI-CTCAE v.4.03) and for laboratory assessments that include biochemistry, hematology, urinalysis; special safety assessments that include the regular monitoring and recording of blood glucose, insulin, HbA1c, GH and IGF-1, thyroid and liver function tests, gallbladder examinations and ECGs. Concomitant medications/Significant nondrug therapies will be assessed
- Change in scores as measured by AcroQoL, EQ-5D-5L |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- from study baseline to week 36
- at week 12 and 24 overall and at screening
- at week 12,24 and 36 overall and at screening
- from study enrollment until the safety follow-up
- from baseline to weeks 12, 24 and 36
For extension phase:
- at weeks 48, 60 and 72
- at weeks 48, 60 and 72
- at weeks 48, 60 and 72
- from study enrollment until the safety follow-up
- from baseline to week 72 and from week 36 to week 72 |
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| 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 |
| Argentina |
| Belgium |
| Brazil |
| China |
| Colombia |
| France |
| Germany |
| Hungary |
| Italy |
| Mexico |
| Portugal |
| Sweden |
| Turkey |
| United Kingdom |
| Venezuela, Bolivarian Republic of |
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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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Completion of the study will occur when all patients have completed their study completion visit and the follow up visit or have discontinued early.
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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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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