| 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 |
| Acromegaly is a hormonal disorder mainly resulting from a tumor in the pituitary gland, leading to excess of growth hormone |
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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 | 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 assess maintenance of biochemical control of octreotide capsules compared to parenteral SRLs in patients with acromegaly, who previously demonstrated biochemical control on both treatments.
• To assess maintenance of biochemical control of octreotide capsules in patients with acromegaly, who previously tolerated and demonstrated biochemical control on SRL injections (FDA objective)
• To assess symptomatic response to octreotide capsules compared to parenteral SRLs.
• To assess patient reported outcome (PRO) in patients treated with octreotide capsules compared to parenteral SRLs.
• To evaluate the safety profile of octreotide capsules compared to parenteral SRLs. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Withdrawal Phase Sub-Study
The objective of the Withdrawal sub-study phase is to assess evidence of active disease and the requirement for chronic treatment in patients previously treated with octreotide capsules in the RCT phase.
Primary Endpoint
• Number of and proportion of patients with evidence of active disease anytime throughout the Withdrawal phase sub-study, of those patients who participated in the Withdrawal phase sub-study (including those
patients who met the first criteria (IGF-1≥1.3 X ULN at the last assessment prior to end of the RCT phase (visit week 58))
Secondary Endpoints
• Percent Change in IGF-1 levels from the last assessment during the RCT phase (week 62, or if missing an earlier assessment not earlier than week 58), on octreotide capsules, to last assessment during the
Withdrawal phase sub-study, off drug.
• Time to initial evidence of active disease |
|
| E.3 | Principal inclusion criteria |
1. Adult subjects, aged 18 to 75 years old, inclusive, at the Screening visit.
2. Patients with acromegaly, defined as documented evidence of GH-secreting pituitary tumor that is abnormally responsive to an oral glucose tolerance test or abnormal IGF-1 levels (>1 x ULN), any time in the past, who are currently receiving parenteral SRLs (octreotide or lanreotide but not pasireotide) for at least 6 months with a stable dose for at least the last four months.
3. Documented biochemical control of their acromegaly on the current dose of SRL (IGF 1 < 1.3 x ULN and mean integrated GH < 2.5 ng/mL over two hours) based on Screening assessment.
4. Patients able and willing to comply with the requirements of the protocol at the time of Screening.
5. Women who are of childbearing potential should use an acceptable method for birth control. Acceptable methods include hormonal contraception (oral contraceptives as long as on stable dose, patch, implant, and injection), intrauterine devices, or double barrier methods (e.g. vaginal diaphragm/ vaginal sponge plus condom, or condom plus spermicidal jelly), sexual abstinence or a vasectomized partner. Women may be surgically sterile or at least 1 year post-last menstrual period. Women taking oral contraception containing levonorgestrel should either change treatment (at least one month prior to first study medication dose) or use a mechanical barrier method.
6.Patients able to understand and sign written informed consent to participate in the study.
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|
| E.4 | Principal exclusion criteria |
1. Patients taking injections of long-acting SRLs less frequently than once every eight weeks (dosing interval > 8 weeks).
2. Patients who previously participated in CH-ACM-01.
3.Symptomatic cholelithiasis.
4. Received pituitary radiotherapy within five years prior to screening (including total body, head and neck or stereotactic radiotherapy).
5. Undergone pituitary surgery within six months prior to screening or have elected surgery planned within the course of the core study.
6. High-risk pattern of pituitary tumor location on pituitary magnetic resonance imaging (MRI)/Computed tomography (CT) as per medical history or most recent MRI/CT.
7.History of unstable angina or acute myocardial infarction within the 12 weeks preceding the screening visit or other clinically significant cardiac disease at the time of screening as judged by the Principal Investigator.
8. Any clinically significant uncontrolled nervous system, gastrointestinal (GI), renal, pulmonary, or hepatic concomitant disease that in the Investigator’s opinion would preclude patient participation.
9.Evidence of active malignant disease or malignancies diagnosed within the previous year (except for basal cell carcinoma and uncomplicated – up to stage 1 squamous cell carcinoma that has been excised and cured).
10.Known allergy or hypersensitivity to any of the test compounds or materials.
11.Known uncontrolled diabetes defined as having a fasting glucose >150 mg/dL (8.3 mmol/L) or glycosylated hemoglobin (HbA1c)> = 8% (patients can be rescreened after diabetes is brought under adequate control, or in case HbA1c < 8%).
12.Known defects in visual fields due to optic chiasmal compression or other neurological signs, related to the pituitary tumor mass. Patients with long standing (>12 months), fixed, minor defects may be considered on a case-by-case basis after consultation with the medical monitor.
13.Female patients who are pregnant or lactating or intending to become pregnant during the study.
14.Known history of immunodeficiency (e.g., HIV positive).
15.ALT, AST or ALP > 3 ´ ULN or Total Bilirubin >1.5 x ULN.
16.Undergone major surgery/surgical therapy for any cause within four weeks prior to enrollment or planned procedure during the study.
17.Known hypothyroidism or hypocortisolism not adequately treated with a stable dose of thyroid or steroid hormone replacement therapy for > =12 weeks.
18.Any condition that may jeopardize study participation (e.g., clinically significant abnormal screening clinical or laboratory finding during screening), the interpretation of study results or may impede the ability to obtain informed consent (e.g., mental condition).
19.History of illicit drug or alcohol abuse within five years.
20.Intake of an investigational drug within 30 days prior to initiation of study treatment.
21.Treatment with pegvisomant within 12 weeks before the screening visit.
22.Treatment with dopamine agonists within 6 weeks before the screening visit.
23.Treatment with pasireotide within 12 weeks before the screening visit. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint (based on EMA advice)
• The proportion of patients who are biochemically controlled throughout the RCT phase. A patient will be considered biochemically controlled if their IGF-1 Time Weighted Average (TWA), during the RCT phase is < 1.3 x ULN.
Additional Primary Endpoints (for FDA)
• Run-in phase - Proportion of patients biochemically controlled at the end of the Run-in phase defined as IGF-1 <1.3 × ULN (based on the average of week 24 and week 26).
• RCT phase - Proportion of patients on octreotide capsules who are biochemically controlled at the end of the RCT phase, defined as IGF-1 <1.3 × ULN (based on the average of week 62 and week 58). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
•The proportion of patients who are biochemically controlledthroughout the RCT phase. A patient will be considered biochemically controlled if their IGF-1 TWA during the RCT phase is < 1.3 × ULN (FDA
endpoint).
•Proportion of patients who are clinically and biochemically controlled at the end of the RCT phase (week 62/EOT). Patients will be considered controlled if they meet both of the following criteria:
-Biochemically controlled if their IGF-1 TWA during the RCT phase is < 1.3 x ULN.
-Clinical control defined as maintained or reduced AIS score at week 62/EOT as compared to week 26 (start of RCT).
• Proportion of patients who maintain or reduce the overall number of active acromegaly symptoms, at the end of the RCT phase (week 62/EOT), compared to week 26 (start of RCT).
• Proportion of patients who maintain or improve their overall AIS score at the end of the RCT phase (improvement defined as a reduction of at least one point in the AIS score), compared to week 26 (start of RCT)
• Acromegaly Treatment Satisfaction Questionnaire (ACRO-TSQ) at the end of the RCT phase.
• Proportion of patients of those completing the RCT phase (at a time octreotide capsules were not commercially available at the specific country), who enter the Study Extension phase, overall and by treatment group.
• Change from the start of the randomized phase of the study (week 26) through the end of the RCT (week 62) for IGF-1.
• Change from the start of the randomized phase of the study (week 26) to end of the RCT (week 62) in mean integrated GH. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | Yes |
| 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 | Yes |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Injectable Somatostatin Receptor Ligands - SRLs (Octreotide LAR or Lanreotide) |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
| Austria |
| France |
| Germany |
| Hungary |
| Italy |
| Lithuania |
| Netherlands |
| Poland |
| Romania |
| Spain |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 8 |
| 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 | 8 |
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