| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| with Chronic Kidney Disease Stage V on dialysis with hyperphosphataemia and dyslipidaemia |
| In Dialisi per malattia renale cronica allo stadio V con iperfosfatemia e didlipidemia concomitante |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10038444 |
| E.1.2 | Term | Renal failure chronic |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective
The primary objective of this study is to demonstrate the efficacy of a range of fixed doses of MCI-196 compared to placebo in the control of serum phosphorus and serum LDL-C in subjects with Chronic Kidney Disease Stage V on dialysis |
| L'obiettivo primario dello studio e' di dimostrare l'efficacia di MCI-196 in piu' dosi fisse rispetto al placebo nel controllo dei livelli sierici di fosforo e colesterolo LDL nei soggetti in dialisi per malattia renale cronica allo stadio V |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
The secondary objectives include evaluation of further efficacy comparisons of a range of fixed doses of MCI-196 compared to placebo with regard to both hyperphosphataemia and dyslipidaemia. The safety and tolerability of MCI-196 compared to placebo will also be evaluated. |
Obiettivi secondari
Gli obiettivi secondari comprendono la valutazione dell'ulteriore comparazione dell'efficacia di MCI-196 in piu' dosi fisse rispetto al placebo su iperfosfatemia e dislipidemia concomitanti.Verranno valutate anche la sicurezza e la tollerabilita' di MCI-196 rispetto al placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Criteria for Inclusion
A subject will be eligible for participation in this study at screening and baseline (if applicable) if all the following criteria are met:
1. The subject is capable of reading and comprehending the informed consent and complying with study procedures, and provides written informed consent.
2. The subject is male or female, 18 to 80 years of age.
3. The subject has a diagnosis of Chronic Kidney Disease (Stage V) as defined by the K/DOQI Guidelines (i.e. GFR < 15mL/min/1.73m2 or dialysis.)
4. The subject is clinically stable (as judged by the Investigator) on haemodialysis or peritoneal dialysis for at least 3 months prior to screening.
5. The subject has stable phosphate control (as judged by the Investigator) using phosphate-binding medication for at least 3 months prior to screening.
6. The subject is undergoing regular dialysis treatment:
o If the subject is on haemodialysis, this should be scheduled to occur 3 times per week in a hospital or centre setting. The duration must be between 3 to 5 hours or if high-flux dialysis, a minimum of 2.5 hours, depending on the standard of care in each centre.
o If the subject is on peritoneal dialysis, this should be scheduled to be either daily APD (Automated Peritoneal Dialysis) or CAPD (Continuous Ambulatory Peritoneal Dialysis), the latter employing at least 3 bag changes per day (1 bag = 1.5L).
7. The subject has serum phosphorus levels < 2.1 mmol/L (6.5 mg/dL) at screening.
8. The subject has calcium dialysate content between 1.00 and 1.75 mmol/L (2.0 to 3.5 mEq/L), depending on the standard of care in each centre. Calcium dialysate content should remain constant for the duration of the study.
9. The subject is on a stabilised phosphorus diet, as considered appropriate by the physician.
10. The subject has baseline Kt/V (single pool) of at least 1.2 for haemodialysis subjects, and a weekly Kt/V value of at least 1.8 for peritoneal dialysis subjects.
11. The subject, if female and of child-bearing potential, has a negative serum pregnancy test. Sexually active females must agree to take appropriate steps not to become pregnant during the course of the clinical study. Specifically, to participate in this study, sexually active females must be 2 or more years post-menopausal, surgically sterilized, or using an accepted form of contraception (oral contraceptives for at least 3 months or an intrauterine device for at least 2 months prior to the start of the screening visit or various barrier methods, such as diaphragm or combination condom and spermicide).
12. Male subjects must agree to use appropriate contraception during the course of the clinical study.
Additional Criteria for Randomisation at Baseline
13. The subject has a serum phosphorus level that is ≥ 2.10 mmol/L (6.5 mg/dL) and is at least 15% greater than at the serum phosphorus level measured at the visit at week -4 (for all patients), after the completion of the washout periods.
OR
The serum phosphorus level is ≥ 2.58 mmol/L (8.0 mg/dL) at any time during the phosphate binder washout period.
14. The subject has serum LDL-C level ≥ 1.82 mmol/L (70 mg/dL). |
Criteri di inclusione
I soggetti saranno eleggibili per partecipare se alla valutazione di screening e al basale (se applicabile), soddisferanno i seguenti criteri:
1. Capacita' di leggere e comprendere il consenso informato e di aderire alle procedure dello studio, nonche' di accordare il consenso informato scritto.
2. Sesso maschile e femminile ed eta' compresa tra 18 e 80 anni.
3. Diagnosi di malattia renale cronica (stadio V), definita secondo le linee guida K/DOQI (ossia VFG <15 ml/min/1,73m2 o dialisi).
4. Soggetti clinicamente stabili (a giudizio dello sperimentare) in emodialisi o dialisi peritoneale da almeno 3 mesi prima dello screening.
5. Stabile controllo del fosfato (a giudizio dello sperimentare) mediante l'assunzione di farmaci leganti il fosfato per almeno 3 mesi prima dello screening.
6. Soggetti sottoposti a dialisi regolare:
o se in emodialisi, questa deve essere ripetuta 3 volte alla settimana presso un ospedale o un centro dialisi. La durata deve essere di 3 - 5 ore o, per l'emodialisi ad alto flusso, di un minimo di 2,5 ore, a seconda del protocollo adottato in ciascun centro.
o se in dialisi peritoneale, questa deve essere una APD giornaliera (dialisi peritoneale automatizzata) oppure CAPD (analisi peritoneale ambulatoriale continua); quest'ultima deve prevedere il cambio di almeno 3 sacche al giorno (1 sacca = 1.5l).
7. Livello di fosforemia sierica < 2,1 mmol/l (6,5 mg/dl) allo screening.
8. Contenuto di calcio nel dialisato compreso tra 1 e 1,75 mmol/l (da 2 a 3,5 mEq/l), a seconda del protocollo adottato in ciascun centro. Il contenuto di calcio nel dialisato deve restare costante per l'intera durata dello studio.
9. Soggetti che seguono uno stabile regime dietetico a base di fosforo, come ritenuto appropriato dal medico.
10. Kt/V (pool singolo) basale di almeno 1,2 se in emodialisi, e valore settimanale del Kt/V di almeno 1,8 se in dialisi peritoneale.
11. Donne in eta' fertile, negative al test di gravidanza nel siero. Le donne sessualmente attive devono acconsentire ad adottare le necessarie misure anticoncezionali per l'intera durata dello studio clinico. In particolare, per partecipare allo studio, le donne sessualmente attive devono essere in post-menopausa da 2 o piu' anni, essere state sottoposte a sterilizzazione chirurgica o adottare metodi contraccettivi approvati (contraccettivi orali da almeno 3 mesi o dispositivo intrauterino da almeno 2 mesi prima dell'inizio della visita di screening, oppure altri metodi di barriera, ad es., diaframma o una combinazione di profilattico e spermicida).
12. Soggetti di sesso maschile che accettano di adottare metodi contraccettivi appropriati per l'intera durata dello studio clinico.
Ulteriori criteri per la randomizzazione alla basale
13. Livello di fosforo sierico ≥ 2,10mmol/l (6,5 mg/dl) e perlomeno superiore del 15% al livello misurato alla visita della settimana -4 (tutti i pazienti), dopo il termine dei periodi di washout.
OPPURE
Livello di fosforo sierico ≥ 2,58 mmol/l (8 mg/dl) in qualsiasi momento del periodo di washout dal legante il fosfato.
14. Livello di colesterolo LDL sierico ≥ 1,82 mmol/l (70 mg/dl). |
|
| E.4 | Principal exclusion criteria |
Criteria for Exclusion
A subject meeting any of the following criteria at screening and baseline (if applicable) will be ineligible to participate in this study:
1. The subject has current clinically significant medical comorbidities, which may substantially compromise subject safety, or expose them to undue risk, or interfere significantly with study procedures and which, in the opinion of the Investigator, makes the subject unsuitable for inclusion in the study.
2. The subject has a serum albumin level < 30.0 g/L.
3. The subject has a PTH level >1000pg/mL
4. The subject has a body mass index (BMI)  16.0 kg/m2 or > 40.0 kg/m2.
5. The subject has serum LDL-C level > 4.94 mmol/L (190 mg/dL)
6. The subject has a serum triglycerides level > 6.76 mmol/L (600 mg/dL)
7. The subject has currently, or a history of, significant gastrointestinal (GI) motility problems, including dysphagia or swallowing difficulty, or GI abnormalities such as chronic or severe constipation, sigmoid colitis, ulcers, or major GI surgery.
8. The subject has biliary obstruction or proven liver dysfunction, i.e., hepatitis, cirrhosis, hepatorenal syndrome, or has liver function tests 3 times the normal values for at least 2 of the measurements (ALT, AST, alkaline phosphatase, and gamma-glutamyl-transferase).
9. The subject is known to have a positive test for hepatitis B surface antigen, or HIV 1 and 2 antibodies. The subject is known to have a positive test for hepatitis C antibody with high transaminase (>3 times the upper limit of normal) or PCR positive. Note: Subjects testing positive for Hepatitis C antibody may be included into the study if, in the opinion of the investigator, there is no evidence of active disease present, as confirmed by PCR
10. The subject has a history of clinically significant severe lactose intolerance or sensitivity (the placebo tablets have a high lactose content), as judged by the Investigator.
11. The subject has a history of substance or alcohol abuse within the last year.
12. The subject has seizure disorders.
13. The subject has a history of drug or other allergy that contraindicates their participation.
14. The subject is using any of the following drugs:
• over-the-counter products containing calcium, magnesium and aluminium, and/or nutritional supplements which can not be stopped during the study period
15. The subject has a temporary catheter as a vascular access and is showing active signs of inflammation or infection as a result of this.
16. The subject has participated in a clinical study with any experimental medication in the last 30 days, or an experimental biological product within the last 90 days, prior to signing of informed consent.
17. The subject has had prior exposure to MCI-196 in the past 12 months.
18. If on peritoneal dialysis, the subject has a recent history of peritonitis (within the previous 3 months). |
Criteri di esclusione
I soggetti, che, alla valutazione di screening e al basale (se applicabile) non soddisfano uno dei seguenti criteri, non saranno eleggibili per partecipare a questo studio:
1. Presenza di comorbidita' clinicamente significativa, tale da compromettere sostanzialmente la sicurezza del paziente, o da esporlo ad un rischio eccessivo, o da interferire significativamente con le procedure dello studio e che, a giudizio dello sperimentatore, rappresentano una controindicazione all'ammissione allo studio.
2. Livello di albumina sierica <30 g/l.
3. Livello di PTH >1000 pg/ml
4. Indice di massa corporea (IMC) 16 kg/m2 oppure >40 kg/m2.
5. Livello sierico di colesterolo LDL >4,94 mmol/l (190 mg/dl).
6. Livello sierico di trigliceridi > 6,76 mmol/l (600 mg/dl).
7. Anamnesi presente o pregressa di problemi di motilita' gastrointestinale (GI), comprese disfagia o deglutizione difficoltosa, oppure altre alterazioni GI, come stipsi cronica o severa, colite del sigmoide, ulcera od importante chirurgia GI.
8. Presenza di occlusione biliare o insufficienza epatica accertata, cioe' epatite, cirrosi, sindrome epatorenale, oppure valori di 3 volte superiori ai valori normali in almeno due parametri di funzionalita' epatica (ALT, AST, fosfatasi alcalina e gamma-glutamil transferasi).
9. Positivita' agli anticorpi anti-HBsAg oppure anti-HIV-1 e 2. Positivita' agli anticorpi anti-HCV associata ad elevati valori di transaminasi (>3 volte il limite superiore della norma) oppure positivita' alla PCR. Nota: i soggetti positivi agli anticorpi anti-HCV possono essere ammessi allo studio se lo sperimentatore ritiene che non vi e' evidenza di patologia in atto, confermata dalla PCR.
10. Anamnesi di intolleranza o sensibilita' grave al lattosio, clinicamente significativa come rilevato dello sperimentatore; (le compresse di placebo hanno un elevato contenuto di lattosio).
11. Anamnesi di abuso di sostanze o di alcool nell'ultimo anno.
12. Presenza di disturbi epilettici convulsivi.
13. Anamnesi di allergia ai farmaci o altri tipi di allergia, che rende controindicata la partecipazione.
14. Assunzione dei seguenti farmaci:
• prodotti da banco contenenti calcio, magnesio e alluminio, e/o supplementi alimentari, la cui assunzione non puo' essere interrotta per la durata dello studio
15. Presenza di catetere temporaneo per l'accesso vascolare con segni concomitanti di infiammazione o infezione da catetere in atto.
16. Precedente partecipazione ad uno studio clinico con farmaci sperimentali nei 30 giorni, oppure con un prodotto biologico sperimentale nei 90 giorni immediatamente precedenti la firma del consenso informato.
17. Precedente esposizione a MCI-196 negli ultimi 12 mesi.
18. Anamnesi recente di peritonite nei soggetti in dialisi peritoneale (nei 3 mesi precedenti lo screening). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints
The co-primary endpoints are the mean change in serum phosphorus and the mean percent change in serum LDL-C from Baseline (week 0) to end of week 12 (or LOCF). |
End-point primari
Gli end-point coprimari sono la variazione media nel fosforo sierico e la variazione percentuale media del colesterolo LDL sierico dal basale (settimana 0) alla fine della 12ª settimana (o LOCF). |
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| - Stesso farmaco ad altro dosaggio |
| - same IMP used at different dosage |
|
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
| Completamento dei 625 Pazienti da arruolare |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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