| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Fragile X syndrome |
| Síndrome X Frágil |
|
| E.1.1.1 | Medical condition in easily understood language |
| Fragile X Syndrome |
| Síndrome X Frágil |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| 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 | 10017324 |
| E.1.2 | Term | Fragile X syndrome |
| 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 |
To evaluate the long-term safety and tolerability of AFQ056 in adolescent patients with FXS as assessed by:
-Incidence and severity of adverse events and serious adverse events
-Changes in vital signs, laboratory assessments, and ECGs
-Monitoring the hypothalamic-pituitary-adrenal/thyroid axis function and childhood developmental milestones |
Evaluar la seguridad y tolerabilidad a largo plazo de AFQ056 en pacientes adolescentes con SXF según la evaluación de:
-La incidencia y gravedad de los acontecimientos adversos y acontecimientos adversos graves.
-Cambios en las constantes vitales, pruebas analíticas y ECG.
-Controlar la función del eje hipotalámico-hipofisario-adrenal/tiroideo y las etapas de desarrollo en la niñez. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the long-term efficacy of AFQ056 treatment in both FM (Fully Methylated) and PM (Partially Methylated) patients with FXS as assessed by:
-Change from baseline in the Aberrant Behavior Checklist ? Community edition (ABC-C) total score and subscale scores
-Rating of global improvement of symptoms in Fragile X patients using the Clinical Global Impression - Improvement (CGI-I) scale.
-Change from baseline in the Repetitive Behavior Scale ? Revised (RBS-R) total score and subscale scores
-Change from baseline in the Social Responsiveness Scale (SRS) total score
-To collect pharmacokinetic data of AFQ056 in the target patient population |
Evaluar la eficacia a largo plazo del tratamiento con AFQ056 en pacientes con el gen TM (totalmente metilado) y PM (parcialmente metilado) con SXF según la evaluación de:
-Cambio respecto a la visita basal en la puntuación total y puntuaciones de las subescalas en la Lista de de Conductas Aberrantes ? Edición Comunidad (ABC-C).
-Valoración de la mejoría global de los síntomas en pacientes con síndrome X frágil mediante la escala Impresión Clínica Global-Mejoría (ICG-M).
-Cambio respecto a la visita basal en la puntuación total y puntuaciones de las subescalas de los Síntomas de Conductas Repetitivas ? Revisada (RBS-R).
-El cambio respecto a la visita basal en la puntuación total de la Escala de Receptividad Social (SRS).
-Recoger datos farmacocinéticos de AFQ056 en la población de de pacientes seleccionados para este subestudio. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Group 1 patients:
-Must have completed the CAFQ056B2214 core study within one week of enrollment into the open-label study
-Has a caregiver who spends, on average, at least 6 hours per day with the patient , who is willing to and capable of supervising treatment, providing input into efficacy and safety assessments, and accompanying the patient to study visits.
Group 2 patients:
-Must meet one of the following conditions:
o completed Study CAFQ056B2131
o completed Study CAFQ056B2214 but enrollment into the current study was delayed for more than a week
o discontinued prematurely from Study CAFQ056B2214 due to intolerability of the dosage in the patient?s assigned treatment group
-Has a caregiver who spends, on average, at least 6 hours per day with the patient , who is willing to and capable of supervising treatment, providing input into efficacy and safety assessments, and accompanying the patient to study visits
Other protocol-defined inclusion criteria may apply |
Pacientes del grupo 1:
-Deben haber finalizado el estudio principal CAFQ056B2214 durante la semana anterior a la inclusión en el estudio abierto.
-Tener un cuidador, o cuidadores, que pase, como media, al menos seis horas al día con el paciente, y que según el criterio del investigador, sea una fuente fiable de información relativa al paciente y a la gravedad de su enfermedad.
Pacientes del grupo 2
-Deben cumplir al menos una de las condiciones siguientes:
a. Haber finalizado el estudio CAFQ056B2131.
b. Haber finalizado el estudio CAFQ056B2214, aunque la inclusión en este estudio se retrasara más de una semana.
c. Haberse retirado de forma prematura del estudio CAFQ056B2214 debido a intolerabilidad a la dosis en el grupo de tratamiento asignado al paciente.
-Tener un cuidador, o cuidadores, que pase, como media, al menos seis horas al día con el paciente, y que según el criterio del investigador, sea una fuente fiable de información relativa al paciente y a la gravedad de su enfermedad.
Ver protocolo, sección criterios de inclusión para más detalles. |
|
| E.4 | Principal exclusion criteria |
? Discontinuation from CAFQ056B2214 or CAFQ056B2131 studies due to safety reasons
? Female patients who are sexually active at any time during the study
? Any advanced, severe or unstable disease
? History and/or presence of schizophrenia, bipolar disease, psychosis, confusional states and/or repeated hallucinations as per DSM-IV criteria
? History of suicidal behavior or considered a high suicidal risk
? History of severe self-injurious behavior
? History of uncontrolled seizure disorder or resistant to therapy within the past 2 years (Patients who are clinically stable under anti-convulsant therapy for the past 2 years are not excluded)
? History of clinically significant allergies requiring hospitalization or non-inhaled corticosteroid therapy (asthma, anaphylaxis, etc.)
? History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether or not there is evidence of local recurrence or metastases
? patients who are using (or used within 6 weeks before baseline) digoxin or warfarin
? Using (or used within 6 weeks before randomization) concomitant medications that are potent inhibitors or inducers of CYP3A4
? Using glutamatergic agents (riluzole, memantine, etc.) or lithium within 6 weeks of baseline
? patients who weigh less than 32 kg (= 10th percentile of body weight for a 12-year old child)
Other protocol-defined exclusion criteria may apply |
-Retirada de los estudios CAFQ056B2214 o CAFQ056B2131 por motivos de seguridad
-Las pacientes sexualmente activas en cualquier momento durante el estudio.
-Cualquier enfermedad avanzada, grave o inestable
-Antecedentes y/o presencia de esquizofrenia, enfermedad bipolar, psicosis, estados de confusión y/o alucinaciones repetidas según los criterios del Manual diagnóstico y estadístico de los trastornos mentales (DSM-IV).
-Antecedentes de conducta suicida o considerada de un alto riesgo suicida.
-Antecedentes de conducta autolesiva severa.
-Antecedentes de trastorno convulsivo no controlado o resistente al tratamiento durante los 2 últimos años (no se excluyen los pacientes clínicamente estables con tratamiento anticonvulsivo durante los 2 últimos años).
-Antecedentes de alergias clínicamente significativas que precisen hospitalización o tratamiento con corticosteroides no inhalados (asma, anafilaxia, etc.).
-Antecedentes de cáncer de cualquier sistema orgánico (salvo carcinoma cutáneo de células basales localizado), tratado o no tratado, durante los últimos 5 años, independientemente de que existan o no pruebas de recurrencia local o metástasis.
-Pacientes que estén utilizando (o hayan utilizado durante las 6 semanas antes de la basal) de forma concomitante inhibidores potentes o inductores de CYP3A4
-Pacientes que estén utilizando (o hayan utilizado durante las 6 semanas antes de la basal) digoxina o warfarina.
-Pacientes que estén utilizando fármacos glutamatérgicos (riluzol, memantina, etc.) o litio durante las 6 semanas anteriores a la basal (Remítase al Anexo 2 para un listado de la medicación).
-Pacientes que pesen menos de 32 kg (= percentil 10 de peso corporal de un niño de 12 años).
Ver protocolo, sección criterios de exlusión para más detalles. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Number of patients having any adverse events (AE) by primary
system organ class and preferred term during the 24 months of thestudy.
Adverse events will be summarized by presenting the number of patientshaving any AE by primary system organ class and/or preferred term.
2) Changes in vital signs.
Pulse and Blood pressure will be taken sitting after five minutes.
Temperature will also be taken.
3) Changes in weight.
Body weight (to the nearest 0.1 kilogram in indoor clothing, but without shoes) will be measured.
4) Changes in height.
Height in centimeters (cm) will be measured.
5) Changes in standard laboratory assessments: change in standard hematology. Standard hematology with differential (red blood cell count, white blood cell count, platelet count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, red blood cell morphology, and white blood cell differential) will be measured.
6) Changes in standard laboratory assessments: change in standard chemistry. Standard chemistry with albumin, alkaline phosphatase, amylase, total bilirubin, calcium, cholesterol, creatine, creatine kinase, gammaglutamyltransferase, glucose, lipase, lactate dehydrogenase, inorganic phosphorus, magnesium, potassium, total protein, aspartate aminotransferase, alanine aminotransferase, sodium, triglycerides, urea and uric acid will be measured.
7) Changes in standard laboratory assessments: change in standard urinalysis.
Specific gravity, bilirubin, blood, glucose, ketones, pH, protein and
urobilinogen will be measured.
8) Changes in hormonal parameter concentrations to evaluate
hypothalamic-pituitary-adrenal (HPA) axis.
Follicle-stimulating Hormone (FSH), Luteinizing Hormone (LH), Oxytocin, Prolactin, Thyroxine-binding Globulin (TBG), Thyroid-stimulating Hormone (TSH) and Thyroxine (T4) concentrations will be measured by a specialized central laboratory.
9) Changes in ECGs.
Standard 12 lead ECGs will be performed. A central facility will be used for the interpretation and analysis of the ECGs. ECG abnormalities will be assessed and QTc intervals will be reported using summary statistics for change from baseline values by visit.
10) Change in Tanner staging score.
Tanner staging is a well-established scale of physical development that quantifies primary and secondary sex characteristics such as the size of the breasts, genitalia, and development of pubic hair (from Tanner stage I to Tanner stage V depending on the physical development). It is assessed by the clinician during physical examination. Tanner staging scores will be summarized. |
-La incidencia y gravedad de los acontecimientos adversos y acontecimientos adversos graves.
-Cambios en las constantes vitales, peso, altura, pruebas analíticas y ECG.
-Controlar la función del eje hipotalámico-hipofisario-adrenal/tiroideo y las etapas de desarrollo en la niñez. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Baseline, week 1, 2, 3, 4, 6, 8, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and/or upon and 1 week after completion/early discontinuation (ED)
2),3) Screening for group 2 (up to -4 weeks), baseline, week 2, 4, 8, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and/or upon and 1 week after completion/ED
4) Screening for group 2 (up to -4 weeks), baseline for group 1, week 26, 52, 78, 104, every 26 weeks thereafter and/or upon completion/ED
5),6),7),8) Screening (for group 2 only - up to -4 weeks), week 4, 12, 52, 104 and upon completion/ED
9) Baseline, week 4, 12, 52, 78, 104, every 26 weeks thereafter and/or upon completion/ED
10) Baseline, week 26, 52, 78, 104 and upon completion/ED |
1) Basal, semana 1, 2, 3, 4, 6, 8, 12, 26, 39, 52, 65, 78, 91, 104, cada 13 semanas después y/o hasta 1 semana después de visita de finalización (VF) o discontinuación prematura (DP).
2),3) Visita 1 para el grupo 2 (hasta -4 semanas), basal, semana 2, 4, 8, 12, 26, 39, 52, 65, 78, 91, 104, cada 13 semanas después y/o hasta 1 semana después de VF/DP
4) Visita 1 para grupo 2 (hasta -4 semanas), basal para grupo 1, semana 26, 52, 78, 104, cada 26 semanas después y/o hasta 1 semana después de VF/DP
5),6),7),8) Visita 1 (sólo para el grupo 2 - hasta -4 semanas), semana 4, 12, 52, 104 y hasta VF/DP
9) Basal, semana 4, 12, 52, 78, 104, cada 26 semanas después y/o hasta 1 semana después de VF/DP
10) Basal, semana 26, 52, 78, 104 y hasta VF/DP |
|
| E.5.2 | Secondary end point(s) |
1) Change in the Aberrant Behavior Checklist-Community edition (ABC-C)
The ABC-C is a symptom checklist for assessing problem behaviors of children and adults with intellectual disability. The ABC-C is comprised of 5 sub-scales (irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity and inappropriate speech) plus total score. The questionnaire is completed by the caregiver by attributing a score from 0 (?not a problem?) to 3 (?problem is severe in degree?) to each item of the questionnaire; the total score ranks from 0 to 174. Summary and change from baseline in the ABC-C total and subscale scores will be reported.
2) Change in the Clinical Global Impression Score ? Severity/Improvement (CGI-S/I) scale.
The CGI-I is used to assess treatment response in psychiatric patients. The scale is divided into two parts, one assessing the severity of illness (CGI-S) and one assessing the improvement (CGI-I). It is a clinician-rated scale. The CGI-I reports the global changes of the symptoms rated on a seven-point scale (from ?very much improved? to ?very much worse?). CGI-I will be summarized by visit. CGI-I will be evaluated using the extension study baseline visit as the reference visit.
3) Change in the Repetitive Behavior Scale ? Revised (RBS-R).
The RBS-R is a rating tool that captures the breadth of repetitive behavior: ritualistic behavior, sameness behavior, stereotypic behavior, self-injurious behavior, compulsive behavior, and restricted interests. Every behavior falling into one of the above categories is rated from 0 (behavior does not occur) to 3(behavior occurs and it is a severe problem). The total score ranks from 0 to 129. It is a questionnaire filled by the caregivers.
4) Change in the Social Responsiveness Scale (SRS) total score.
The SRS distinguishes autism spectrum conditions from other psychiatric conditions by identifying the presence and extent of autistic social impairment and by assessing social awareness, social information processing, capacity of reciprocal social communication, social anxiety/avoidance, and autistic preoccupations and traits. Every behavior is rated from 0 (not true) to 3 (almost always true) by the caregiver. The total score ranks from 0 to 195.
5) Assessment of pharmacokinetic (PK) parameters: Plasma concentration levels of AFQ056
Analytes: parent drug AFQ056 concentrations in plasma will be determined by a validated LC-MS-MS method.
The data collected in the study will not allow the calculation of conventional PK parameters by non compartmental analysis. The data will be summarized and descriptive statistics of timed plasma concentrations levels will be provided. The pharmacokinetic data of this study may be combined with data from other studies to perform a population PK analysis which will follow the broad principles outlines in the FDA Guidance for Industry: Population Pharmacokinetic. |
Evaluar la eficacia a largo plazo del tratamiento con AFQ056 en pacientes con el gen TM (totalmente metilado) y PM (parcialmente metilado) con SXF según la evaluación de:
-Cambio respecto a la visita basal en la puntuación total y puntuaciones de las subescalas en la Lista de de Conductas Aberrantes ? Edición Comunidad (ABC-C).
-Valoración de la mejoría global de los síntomas en pacientes con síndrome X frágil mediante la escala Impresión Clínica Global-Mejoría (ICG-M).
-Cambio respecto a la visita basal en la puntuación total y puntuaciones de las subescalas de los Síntomas de Conductas Repetitivas ? Revisada (RBS-R).
-El cambio respecto a la visita basal en la puntuación total de la Escala de Receptividad Social (SRS)
-Recoger datos farmacocinéticos de AFQ056 en la población de de pacientes seleccionados para este subestudio. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Baseline, week 4, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and upon completion/early discontinuation.
2) Baseline, week 4, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and upon completion/early discontinuation.
3) Baseline, week 4, 39, 52, 78, 104, and upon completion/early discontinuation
4) Baseline, weeks 4, 39, 52, 78, 104, and upon completion/early discontinuation)
5) Week 4, 12, 52, and 104. |
1) Basal, semana 4, 12, 26, 39, 52, 65, 78, 91, 104, cada 13 semanas después y hasta VF/DP
2) Basal, semana 4, 12, 26, 39, 52, 65, 78, 91, 104, cada 13 semanas después y hasta VF/DP
3) Basal, semana 4, 39, 52, 78, 104, y hasta VF/DP
4) Basal, semana 4, 39, 52, 78, 104, y hasta VF/DP
5) Semana 4, 12, 52, y 104. |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| tolerability |
| Tolerabilidad |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 13 |
| 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 |
| Australia |
| Canada |
| Denmark |
| France |
| Germany |
| Israel |
| Italy |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
|
| 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
|
| Last Patient Last Visit |
| Último paciente última visita |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 26 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 26 |
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