| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| adrenal insufficienty |
| insufficienza surrenalica |
|
| E.1.1.1 | Medical condition in easily understood language |
| adrenal insufficienty |
| insufficienza del surrene |
|
| 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 | 10001367 |
| E.1.2 | Term | Adrenal insufficiency |
| E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
|
| 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 compare the effect of dual-release hydrocortisone with immediate-release glucocorticoid replacement therapy on glucose control (HbA1c) in patients with adrenal insufficiency and concomitant diabetes mellitus. |
| valutare se la terapia con idrocortisone a rilascio modificato ha dei vantaggi in termini di miglioramento del compenso glicemico rispetto alla terapia sostitutiva con glucocorticoidi a breve emivita nei pazienti con iposurrenalismo e diabete mellito. |
|
| E.2.2 | Secondary objectives of the trial |
to evaluate the impact of hydrocortisone on release modified compare to short-lived glucocorticoids in terms of insulin sensitivity, glicemic variability, lipid profile, anthopometric parameters and body composition, blood pressure and heart rate, bone metabolism and quality of life. The safety objectives are:
1. Number of hypoglycaemic episodes
2. hospitalization for acute adrenal crisis |
valutare l'impatto dell'idrocortisone a rilascio modificato rispetto ai glucocorticoidi a breve emivita nei pazienti con iposurrenalismo e diabete mellito in termini di sensibilit¿ insulinica, variabilit¿ glicemica, profilo lipidico, parametri antropometrici e di composizione corporea, pressione arteriosa e frequenza cardiaca, metabolismo osseo e qualit¿ di vita. Gli obiettivi di sicurezza dello studio sono:
1. numero di episodi ipoglicemici
2. ospedalizzazione per crisi surrenalica acuta |
|
| 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 |
Other types of substudies
Specify title, date and version of each substudy with relative objectives: Biologic substudy, v1 10/11/2016 - Each patient will be submitted, in addition to the dosages provided by the protocol of study, to three additional withdrawals, 10 ml of
blood for each sampling, during visit 0, visit 3, and visit 6. Such a sub-study
provides the optional withdrawal and retention of 30 ml of blood samples (serum and plasma)
for any further evaluations, about any possible important molecules correlated with metabolic and / or endocrine effects of modified release hydrocortisone (eg new biochemical indicators of glycemic remission and / or glycemic variability
and / or bone resorption etc). In addition, such blood samples will be stored for a period of time
of 10 years, at the Endocrinology, Diabetology and Metabolism Laboratory, under the
responsibility of Dr. Spiazzi. At the end of this period of 10 years the blood samples and
the associated data will be destroyed.
|
Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sottostudio biologico, v1 del 10/11/2016. Ciascun paziente verr¿ sottoposto, oltre ai dosaggi previsti dal protocollo di studio, a tre prelievi aggiuntivi, 10 ml di
sangue per ciascun prelievo, nell¿ambito di visita 0, di visita 3 e di visita 6. Tale sottostudio
prevede il prelievo e la conservazione facoltativa di 30 ml di campioni di sangue (siero e plasma)
per eventuali ulteriori valutazioni, qualora dovessero emergere importanti molecole utili a
caratterizzare gli effetti metabolici e/o endocrini del trattamento con idrocortisone a rilascio
modificato (ad es. nuovi indicatori biochimici di compenso glicemico e/o di variabilit¿ glicemica
e/o di riassorbimento osseo etc). Inoltre, tali campioni di sangue verranno conservati per un periodo
di 10 anni, presso il laboratorio di Endocrinologia, Diabetologia e Metabolismo, sotto la
responsabilit¿ della dott.ssa Spiazzi. Al termine di questo periodo di 10 anni i campioni di sangue e
i dati ad essi associati saranno distrutti.
|
|
| E.3 | Principal inclusion criteria |
The inclusion criteria for the participants in this study are as follows:
• Males and females older than 18 years up to 90 years of age (women of childbearing age they will perform a high sensitivity pregnancy test to exclude a pregnancy before being included in the study);
• diagnosis of primitive or secondary adrenal insufficiency;
• Stable substitution treatment (same dosage and same active principle) with glucorticoids for at least 6 months;
- Substitution treatment with L-thyroxin and / or fludrocortisone stable at least 3 months before
enrollment
• Concomitant diagnosis of DMT1 or DMT2, in multiinjection insulin therapy or with Oral hypoglycemic agents.
• Affected at the Hospitals' Diabetes / Endocrinology Outpatient Clinic University of Verona;
• optimization of metabolic control prior to entry into the study in the presence of clinically stable HbA1c values ¿¿(variations of less than 0.3%) in the two controls prior to recruitment, spaced at least 3 months apart;
• Signature of informed consent
|
maschi e femmine di eta’ superiore a 18 anni fino ai 90 anni di età (le donne in età fertile
effettueranno un test di gravidanza ad alta sensibilità per escludere una gravidanza, prima di
essere incluse nello studio); diagnosi di insufficienza surrenalica primitiva o secondaria; trattamento sostitutivo stabile (medesima posologia e medesimo principio attivo) con glucorticoidi da almeno 6 mesi; trattamento sostitutivo con L-tiroxina e/o fludrocortisone stabile da almeno 3 mesi prima dell’arruolamento; diagnosi concomitante di DMT1 o di DMT2, in terapia insulinica multi-iniettiva o con ipoglicemizzanti orali; afferenti presso gli ambulatori di diabetologia/endocrinologia dell’AOUI Verona; • ottimizzazione del controllo metabolico prima dell’ingresso nello studio in presenza di valori di HbA1c clinicamente stabili (variazioni inferiori a 0.3%) nei due controlli precedenti il reclutamento, distanziati tra loro di almeno 3 mesi; firma del consenso informato; |
|
| E.4 | Principal exclusion criteria |
Subjects will be excluded from the study with the following characteristics:
- Pregnant women or fertile age in extroprogestine therapy for contractual purposes;
- breastfeeding women;
- subjects with hypersensitivity to the active substance or to any of the excipients
- Gastrointestinal motility disorders;
- Adrenal insufficiency secondary to the suspension of chronic steroid treatment;
• Cortical-adrenal carcinoma
- Coexistence of other pathologies that may require a treatment cycle high doses of steroids.
|
- donne in gravidanza o in età fertile in terapia estroprogestinica con finalità contracettiva;
- donne in allattamento;
- soggetti con ipersensibilità al principio attivo o ad uno qualsiasi degli eccipienti
- patologie della motilità gastro-intestinale;
- insufficienza surrenalica secondaria alla
sospensione di un trattamento steroideo cronico;
- carcinoma cortico-surrenalico; coesistenza di altre patologie per le quali possa rendersi necessario un ciclo di trattamento steroideo ad elevate dosi |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| For the purpose of evaluating the variation in glycemic charge during treatment with Modified hydrocortisone compared to conventional treatment, the variable being considered will be HbA1c, expressed both in (%) and mmol / mol, measured on visit 3 and on visit 6 |
Ai fini di una valutazione della variazione del compenso glicemico in corso di trattamento con
idrocortisone a rilascio modificato rispetto al trattamento convenzionale, la variabile considerata
sarà l¿HbA1c, espressa sia in (%) sia in mmol/mol, dosata a visita 3 e a visita 6 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| visit 3 and 6 |
| visita 3 e 6 |
|
| E.5.2 | Secondary end point(s) |
| For an assessment of the variation in insulin sensitivity, the variable considered will be (SI) [micromol / min / m2 BSA] derived from hyperinsulinemic euglycemic clamp; Any changes in blood pressure (systolic and diastolic), heart rate, lipid profile (total cholesterol levels, HDL, triglyceridaemia and FFA), body weight, abdominal/hip circumference and body composition (percentage fat mass and lean mass found at impedance), Variations in Bone Neoformation Markers (osteocalcin) and Bone Resorption (CTX) concentrations. To evaluate the change in the quality of life, the score of the AddiQoL questionnaire 30 will be compared ; For the purposes of evaluating the variation of glycemic variability, the variables to be calculated from the continuous glucose monitoring are: AUCG (area under the glucose curve) <70 mg / dl and> 250 mg / dl, LBGI, HBGI , mean (+/- standard deviation) of 24-hour glucose concentrations and MAGE; the number of severe hypoglycaemic episodes (glycaemia <50 mg / dl) will be compared to the glucometer of each subject over the 6 months of each of the two treatments (safety endpoint). Furthermore, the number of hospitalizations for acute adrenal insufficiency will be compared during each of the two treatments (safety endpoint). |
| Per una valutazione della variazione della sensibilit¿ insulinica la variabile considerata sar¿ (SI) [micromol/min/m2 BSA] ricavata dai dati derivati dal clamp euglicemico iperinsulinemico; Verranno valutate eventuali variazioni della pressione arteriosa (sistolica e diastolica), della frequenza cardiaca, del profilo lipidico (livelli di colesterolemia totale, HDL, trigliceridemia e FFA), del peso corporeo, del rapporto circonferenza addominale/fianchi e della composizione corporea (percentuale di massa grassa e massa magra rilevate all¿impedenziometria), variazioni delle concentrazioni dei marker di neoformazione ossea (osteocalcina) e di riassorbimento osseo (CTX). Per la valutazione del cambiamento della qualit¿ di vita err¿ confrontato il punteggio del questionario AddiQoL 30; ai fini della valutazione della variazione della variabilit¿ glicemica, le variabili che verranno calcolate a partire dai dati derivanti dal monitoraggio continuo del glucosio sono: AUCG (area sotto la curva del glucosio) <70 mg/dl e >250 mg/dl, LBGI, HBGI, la media (¿ deviazione standard) delle concentrazioni di glucosio rilevate nelle 24 ore ed il MAGE; verranno confrontati il numero di episodi ipoglicemici severi (glicemia < 50 mg/dl) rilevati al glucometro di ciascun soggetto nell¿arco dei 6 mesi di ciascuno dei due trattamenti (safety endpoint). Inoltre, verr¿ confrontato il numero di ospedalizzazioni per insufficienza surrenalica acuta nel corso di ciascuno dei due trattamenti (safety endpoint). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| visit 2 and 5; visit 0, 3, 6; visit 1ter and 4; visit 1, 1 bis, 1 ter, 2, 3, 3 bis, 3 ter, 4, 5, 6 |
| visita 2 e 5; visita 0, 3, 6; visita 1ter e 4; visita 1, 1 bis, 1 ter, 2, 3, 3 bis, 3 ter, 4, 5, 6 |
|
| 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 | 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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