| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011777 |
| E.1.2 | Term | Cystinosis |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 |
Primary Objective:
To demonstrate superiority of RP103 versus Cystagon® in controlling white blood cell cystine (WBC) levels over 24 hours in patients with cystinosis and to assess long-term safety and tolerability of RP103 |
Obiettivo primario: Dimostrare la superiorità di RP103 rispetto a
Cystagon nel controllo dei livelli di cistina leucocitaria nell’arco delle
24 ore in pazienti affetti da cistinosi. Valutare la sicurezza e la
tollerabilità di RP103 a lungo termine. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
To compare WBC cystine measurements provided by a central
laboratory versus sites’ local (regional, not associated with the
clinical trial) laboratories.
To assess long-term quality of life and sleep using instruments
appropriate to the subjects’ age and region (US or Europe).
To assess subject dosing compliance with two different
cysteamine bitartrate formulations, Q6H immediate-release
Cystagon® versus Q12H delayed-release RP103.
To assess halitosis during Cystagon® and RP103 treatment in a
subgroup of subjects |
Obiettivi secondari: Confrontare le misurazioni di cistina leucocitaria
fornite da un laboratorio centrale con quelle di laboratori locali
(regionali, non associati alla sperimentazione clinica). Valutare la
qualità della vita e del sonno a lungo termine utilizzando strumenti
appropriati per l’età e la regione del soggetto (Stati Uniti o Europa).
Valutare la compliance di assunzione del soggetto con due formulazioni
differenti di cisteamina bitartrato, Cystagon a rilascio immediato Q6H
rispetto a RP103 a rilascio ritardato Q12H. Valutare l’alitosi durante il
trattamento con Cystagon e RP103 in un sottogruppo di soggetti |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male or female with a documented diagnosis of cystinosis.
2. On a stable dose of Cystagon® for at least 21 days prior to
Screening.
3. WBC cystine level > 1 nmol ½ cystine/mg of protein on
average over at least 2 measurements collected during the 2
years prior to Screening.
4. No clinically significant change in liver function tests, i.e. 1.5
times ULN for ALT and AST, and/or 1.5 times ULN for total
bilirubin, within 6 months prior to Screening.
5. No clinically significant change in renal function, i.e.
estimated GFR within 6 months prior to Screening.
6. Must have an estimated GFR > 20 mL/minute/1.73 m2 (using
the equation from Schwartz 2009 J Am Soc Nephrol 20:629-
637) 1.
7. Female subjects who are sexually active and of childbearing
potential, i.e. not surgically sterile (tubal ligation, bilateral
oopherectomy, or hysterectomy) or at least 2 years naturally
postmenopausal must agree to use an acceptable form of
contraception from Screening through completion of the
study. Acceptable forms of contraception for this study
include hormonal contraceptives (oral, implant, transdermal
patch, or injection) at a stable dose for at least 3 months prior
to Screening, barrier (spermicidal condom or diaphragm with
spermicide), IUD, or a partner who has been vasectomized
for at least 6 months.
8. Subject or their parent or guardian must provide written
informed consent and assent (where applicable) prior to
participation in the study.
|
1. Pazienti di sesso maschile o femminile con una diagnosi documentata
di cistinosi. 2. A dose stabile di Cystagon per almeno 21 giorni prima
dello screening. 3. Livello di cistina leucocitaria > 1 nmol ½ cistina/mg
di proteina in una media di almeno 2 misurazioni raccolte durante i 2
anni precedenti allo screening. 4. Nessuna alterazione clinicamente
significativa dei test della funzionalità epatica, vale a dire 1,5 volte
l’ULN per ALT e AST e/o 1,5 volte l’ULN per la bilirubina totale, nei 6 mesi precedenti lo screening. 5. Nessuna alterazione clinicamente
significativa della funzione renale, vale a dire una VFG stimata nei 6
mesi precedenti lo screening. 6. È necessario presentare una VFG
stimata > 20 ml/minuto/1,73 m2 (utilizzando l’equazione di Schwartz
2009 J Am Soc Nephrol 20:629-637) 1. 7. I soggetti di sesso femminile
sessualmente attivi e in età fertile, vale a dire non chirurgicamente
sterili (legamento delle tube, ovariectomia bilaterale o isterectomia) o
naturalmente in postmenopausa da almeno 2 anni, devono acconsentire
a utilizzare un metodo contraccettivo accettabile dal momento dello
screening al completamento dello studio. I metodi contraccettivi
accettabili per questo studio includono contraccettivi ormonali (orale,
impianto, cerotto transdermico o iniezione) a dose stabile per almeno 3
mesi precedenti allo screening, contraccettivi di barriera (preservativo
con crema spermicida o diaframma con spermicida), IUD o partner
vasectomizzato da almeno 6 mesi. 8. Il soggetto o il genitore o il tutore
devono fornire il consenso informato e l’assenso in forma scritta (se
applicabile) prima della partecipazione allo studio. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria:
1. Younger than 12 years of age.
2. Current history of the following conditions or any other
health issues that make it, in the opinion of the Investigator,
unsafe for study participation:
- Inflammatory bowel disease if currently active, or
prior resection of small intestine;
- Heart disease (e.g. myocardial infarction, heart
failure, unstable arrhythmias, or poorly controlled
hypertension) within 90 days prior to Screening;
-Active bleeding disorder within 90 days prior to
Screening;
- History of malignant disease within 2 years prior to
Screening.
3. Hemoglobin level of < 9 g/dL at Screening or, in the opinion
of the Investigator, a hemoglobin level that would make it
unsafe for study participation.
4. Known hypersensitivity to cysteamine and penicillamine.
5. Female subjects who are nursing, planning a pregnancy, or
are known or suspected to be pregnant.
6. Subjects who, in the opinion of the Investigator, are not able
or willing to comply with study requirements. |
1. Pazienti di età inferiore ai 12 anni. 2. Anamnesi corrente delle
seguenti patologie o di altri problemi di salute che, secondo lo
sperimentatore, rendono pericolosa la partecipazione allo studio:
patologia infiammatoria dell’intestino se attualmente attiva o pregressa
resezione dell’intestino tenue; cardiopatia (ad esempio infarto del
miocardio, insufficienza cardiaca, aritmie instabili o ipertensione non
controllata) nei 90 giorni che precedono lo screening; disordine
emorragico attivo nei 90 giorni che precedono lo screening; anamnesi di
patologia maligna nei 2 anni che precedono lo screening. 3. livello di
emoglobina di < 9 g/dl allo screening o, secondo lo sperimentatore, un
livello di emoglobina che renderebbe pericolosa la partecipazione allo
studio. 4. Nota ipersensibilità alla cisteamina e alla penicillamina. 5.
Soggetti di sesso femminile in allattamento, che stanno programmando
una gravidanza o in stato di gravidanza accertata o sospetta. 6. Soggetti
che, secondo lo sperimentatore, non possono o non intendono |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Comparison of steady-state cysteamine-trough WBC cystine
levels between Cystagon® and RP103 over 3 months for each
treatment period.
|
Confronto dei livelli di cistina leucocitaria e di quelli di cisteamina allo
stato stazionario (steady state) tra Cystagon e RP103 nei 3 mesi per ogni
periodo di trattamento. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Months 1,2 and 3 vs Months 5,6 and 7 (Comparing the Cystagon and RP103 3-month treatment periods) |
| Mesi 1,2 e 3 vs mesi 5,6 e 7 (confronto tra i periodi di 3 mesi di trattamento tra CYSTAGON e RP103) |
|
| E.5.2 | Secondary end point(s) |
Safety Endpoints:
- The safety profile of RP103 will be investigated by changes
from the last study visit as noted in the following safety
assessments: physical examination, vital signs, ECG and
clinical laboratory testing. Incidence of adverse event report
(including attribution of treatment-emergent non-serious and
serious adverse events) will be recorded.
Pharmacokinetic Endpoint:
- Halitosis Substudy participants only: Cmax, Tmax and AUCs
for plasma cysteamine and expired air DMS concentrations
will be determined.
Pharmacodynamic Endpoint:
-The WBC cystine content will be measured from samples
collected within 15 minutes pre-dose under Cystagon® or 30
minutes post-dose under RP103 at each study visit.
Exploratory Endpoints:
-Central laboratory versus local laboratory WBC cystine
values.
-The longitudinal change in the use of concomitant gastric
acid reduction therapies, quality of life questionnaires, and
VAS swallowing difficulty and sleep rating scale scores. |
Safety Endpoints: The safety profile of RP103 will be investigated by
changes from the last study visit as noted in the following safety
assessments: physical examination, vital signs, ECG and clinical
laboratory testing. Incidence of adverse event report (including
attribution of treatment-emergent non-serious and serious adverse
events) will be recorded. Pharmacokinetic Endpoint: Halitosis Substudy
participants only: Cmax, Tmax and AUCs for plasma cysteamine and
expired air DMS concentrations will be determined. Pharmacodynamic
Endpoint: The WBC cystine content will be measured from samples
collected within 15 minutes pre-dose under Cystagon or 30 minutes
post-dose under RP103 at each study visit. Exploratory Endpoints:
Central laboratory versus local laboratory WBC cystine values. The
longitudinal change in the use of concomitant gastric acid reduction
therapies, quality of life questionnaires, and VAS swallowing difficulty
and sleep rating scale scores. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Safety and secondary endpoints will be assesed following every pertinent study visit. Unless they discontinue the study, subjects will complete Screening, Day 1, an 8 bi-Monthly (every 2 week) visits, i.e. through Month 7 plus Termination Visit. If study drug is not yet approved , that will be followed by Quarterly visits, up to 24 Months. |
| La sicurezza e gli endpoint secondari saranno valutati dopo ogni visita di studio pertinente. A meno che non si interrompa lo studio, i soggetti completeranno lo Screening, ilgiorno 1, 8 visite bi-mensili (ogni due settimane), vale a dire fino al Mese 7 più la Visita di fine studio. Se il farmaco in studio non è ancora stato approvato, che sarà seguita da visite trimestrali, fino a 24 mesi. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | 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 | 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 | 1 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| United Kingdom |
| United States |
| France |
| Germany |
| Belgium |
| Italy |
| Netherlands |
|
| 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
|
| last visit of last subject undergoing the trial. |
| Ultima Visita Ultimo Paziente |
|
| 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 | 24 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 24 |
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