| 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 |
| L'Acromegalia è un disordine ormonale risultante da una forma tumorale della ghiandola pituitaria che porta ad un eccesso di ormone della crescita. |
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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 | 19.0 |
| 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 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. |
• Valutare il mantenimento del controllo biochimico di octreotide in capsule rispetto a SRL per via parenterale in pazienti con acromegalia che precedentemente hanno dimostrato controllo biochimico con entrambi i trattamenti.
• Valutare la risposta sintomatica a octreotide in capsule rispetto a SRL per via parenterale.
• Valutare gli esiti riportati dai pazienti (PRO) nei pazienti trattati con octreotide in capsule rispetto a SRL per via parenterale.
• Valutare il profilo di sicurezza di octreotide in capsule rispetto a SRL per via parenterale.
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| E.2.2 | Secondary objectives of the trial |
| Not applicable |
| Non applicabile |
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| E.2.3 | Trial contains a sub-study | No |
| 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, 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. |
Per essere eleggibili per l'ingresso nello studio è necessario soddisfare tutti i criteri di inclusione.
1. Soggetti adulti, di età compresa tra 18 e 75 anni inclusi, alla visita di Screening.
2. Pazienti con acromegalia, definita come evidenza documentata di tumore pituitario GH- secernente che presenta una risposta anomala al test di tolleranza del glucosio orale o livelli anomali di IGF-1 (>1 x ULN), in qualsiasi momento nel passato, che attualmente sono in trattamento con SRL per via parenterale (octreotide o lanreotide ma non pasireotide) da almeno 6 mesi e in dosaggio stabile almeno dagli ultimi quattro mesi.
3. Controllo biochimico documentato dell'acromegalia con il dosaggio attuale di SRL (IGF-1 <1.3 x ULN e concentrazione media integrata di GH <2,5 ng/ml nell'arco di due ore) in base alla valutazione di Screening.
4. Pazienti in grado di e disposti ad aderire ai requisiti del protocollo al momento dello Screening.
5. Le donne in età fertile devono utilizzare un metodo contraccettivo accettabile. I metodi accettabili includono contraccezione ormonale (contraccettivi orali, cerotto, impianto ed iniezione), dispositivi intrauterini o metodi a doppia barriera (per esempio diaframma vaginale, spugna vaginale più preservativo o preservativo associato a gel spermicida), astinenza sessuale o partner vasectomizzato. Le donne possono essere chirurgicamente sterili o in periodo post-menopausale da almeno 1 anno. Le donne che assumono contraccettivi orali contenenti levonorgestrel devono cambiare il trattamento (almeno un mese prima dell'assunzione della prima dose di farmaco in studio) o usare un metodo di barriera meccanico.
6. Pazienti in grado di comprendere e firmare un consenso informato scritto alla partecipazione allo studio.
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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.
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 one 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, ALP or GGT > 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. |
Rientrare in uno qualsiasi tra i seguenti criteri escluderebbe un paziente dalla partecipazione allo studio:
1. Pazienti in trattamento con SRL a lunga durata d'azione con dosaggio meno frequente di una volta ogni otto settimane (intervallo di dosaggio > 8 settimane).
2. Pazienti che in precedenza hanno partecipato a CH-ACM-01.
3. Colelitiasi sintomatica.
4. Radioterapia pituitaria ricevuta entro cinque anni prima dello screening (inclusa radioterapia total body, testa e collo o radioterapia stereotassica)
5. Intervento chirurgico all'ipofisi entro sei mesi prima dello screening o intervento chirurgico d'elezione programmato nel corso dello studio principale.
6. Pattern2 ad alto rischio di sede tumorale nell'ipofisi rilevata mediante risonanza magnetica per immagini (RMI) pituitaria/Tomografia computerizzata (TC) in base all'anamnesi medica o a RMI più recente.
7. Anamnesi di angina instabile o infarto miocardico acuto entro le 12 settimane che precedono la visita di screening o altre malattie cardiache clinicamente significative al momento dello screening in base al giudizio dello Sperimentatore principale.
8. Qualsiasi malattia non controllata, clinicamente rilevante a carico del sistema nervoso, gastrointestinale (GI), renale, polmonare, o malattia epatica concomitante che a giudizio dello sperimentatore precluderebbe la partecipazione del paziente.
9. Evidenza di patologia maligna attiva o tumore maligno diagnosticato entro l'anno precedente (eccetto per carcinoma delle cellule basali e carcinoma a cellule squamose non complicato fino allo stadio 1 che sia stato escisso e curato).
10. Nota allergia o ipersensibilità a uno qualsiasi dei composti o materiali sperimentali.
11. Noto diabete non controllato definito come livelli di glucosio a digiuno
>150 mg/dl (8,3 mmol/l) o emoglobina glicosilata (HbA1c) <8% (i pazienti possono essere nuovamente sottoposti a screening dopo che il diabete è stato riportato sotto controllo adeguato, o nel caso in cui HbA1c < 8%).
12. Noti difetti nel campo visivo dovuti a compressione del chiasma ottico o altri segni neurologici, correlati alla massa tumorale ipofisaria. I pazienti con difetti minori, fissi, di lunga durata (> 12 mesi) possono essere considerati caso per caso dopo un consulto con il responsabile medico.
13. Pazienti di sesso femminile in stato di gravidanza, che allattano o che intendono intraprendere una gravidanza durante lo studio.
14. Nota anamnesi di immunodeficienza (per esempio positività al virus HIV).
15. ALT, AST, ALP or GGT > 3 x ULN o bilirubina totale >1,5 x ULN.
16. Intervento chirurgico importante/terapia chirurgica per qualsiasi causa entro
quattro settimane prima dell'arruolamento o della procedura programmata durante lo studio.
17. Noto ipotiroidismo o ipocortisolismo non adeguatamente trattato con una dose stabile di terapia sostitutiva a base di ormoni steroidei o tiroidei per >12 settimane.
18. Qualsiasi condizione che possa mettere a rischio la partecipazione allo studio (esiti clinici o di laboratorio anomali clinicamente rilevanti allo screening), l'interpretazione dei risultati dello studio o possa ostacolare la possibilità di ottenere un consenso informato (per esempio malattia mentale).
19. Anamnesi di abuso di alcol o droghe illecite entro cinque anni.
20. Assunzione di un farmaco sperimentale nei 30 giorni precedenti l'inizio del trattamento in studio.
21. Trattamento con pegvisomant, entro 12 settimane prima della visita di screening
22. Trattamento con agonisti della dopamina, entro 6 settimane prima della visita di screening.
23. Trattamento con pasireotide, entro 12 settimane prima della visita di screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary Endpoint • 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. |
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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) |
| 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 | 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 | 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 | No |
| 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 | 4 |
| 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 |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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