| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10058920 |
| E.1.2 | Term | Restless legs syndrome |
|
| 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 |
The primary objective for the 12-week Titration-/Maintenance Period is:
• To demonstrate superior efficacy of OXN PR compared to PLA in the improvement of symptom severity of RLS as measured by the International Restless Legs Syndrome Study Group Rating Scale (IRLS scale).
The objectives for the open-label Extension Phase are:
• Proportion of subjects with Augmentation according to the MPI Criteria, 2007 (Max Planck Institute Consensus conference) during OXN PR treatment (Expert’s/Investigator’s assessment).
• Assessment of severity of augmentation (ASRS) during OXN PR treatment.
• Tolerability and safety of long-term treatment with OXN PR.
• Long-term efficacy of OXN PR during the open-label Extension Phase in all efficacy variables listed above. |
|
| E.2.2 | Secondary objectives of the trial |
Assessment of:
• improvement of severity of RLS in the CGI severity scale in patients taking OXN PR compared to PLA
• change of severity of RLS during the day at rest (RLS-6-Rating Scale) OXN PR compared to PLA
• change of severity of RLS in the further RLS-6-Rating scales OXN PR compared to PLA
• change in NRS for pain in patient’s legs or arms (RLS pain) OXN PR compared to PLA
• the Responder Rate of subjects with at least 50% improvement in the IRLS scale or ratings “very much” or “much” improved in the CGI scale 2 “change of condition”
• the Remitter Rate IRLS scale 0 or a final IRLS score ≤ 10
• change in disease-specific quality of life (QoL-RLS-Scale)
• change in sleep behaviour of subjects with OXN PR compared to PLA using the MOS sleep scales
• therapeutic effect (based on CGI item 3)
• the Incidence of Augmentation
• severity of augmentation (ASRS) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects at least 18 years or older.
2. Female subjects less than one year post-menopausal must have a negative pregnancy test recorded prior to the first dose of study medication, be non-lactating, and willing to use adequate and highly effective methods of contraception throughout the study. A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilization, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or vasoectomised partner.
3. Diagnosis of RLS (score ≥ 11) according to the “Restless Legs Syndrome Diagnostic Index” (RLS-DI, see Appendix 12.10). In addition, at least one of the criteria 7 “positive family history of the RLS”, 8 “positive response to dopaminergic treatment”, 9 “objective findings of periodic limb movements in polysomnography or actigraphy” must be definitely present or criterion 10 “usual findings in neurological examination” is answered with “no” (Benes & Kohnen, 2008).
4. Patients dissatisfied with any current (lack of efficacy or unacceptable tolerability) or previous (those who stopped previous therapy because of non-efficacy or side effects) drug treatment of RLS who would benefit from an alternative treatment option with OXN PR.
5. Presence of RLS symptoms for at least 6 months.
6. IRLS score at screening Visit (visit 1) of ≥ 15.
7. Onset of RLS symptoms during the day usually (on at least 4 days per week) before 18:00.
8. Subjects must not have received opioid containing medication (including tilidine, tramadol, codeine) for the treatment of RLS and other disorders (pain) on a regular basis at any time before enrolment. Occasional use for treatment of cough/cold, pain etc is acceptable if the last intake was at least 1 month before enrolment.
9. Subjects willing and able to participate in all aspects of the core study, including use of oral medication, completion of subjective evaluations, attending scheduled clinic visits, completing telephone contacts, and compliance with protocol requirements as evidenced by providing written, informed consent and willing to discontinue their current RLS treatment.
10. Subjects taking pre-study, non-opioid analgesics, that are thought to be stable, and are considered necessary for the subject’s welfare, and are anticipated to remain stable throughout the Double-blind Phase of the study, and are to be continued under the supervision of the investigator, are eligible. |
|
| E.4 | Principal exclusion criteria |
1. Secondary RLS due to, e.g. iron deficiency anemia, renal insufficiency, rheumatoid arthritis.
2. RLS associated with previous or concomitant therapy with dopamine D2 receptor antagonists, butyrophenones, metoclopramide, atypical antipsychotics (e.g. olanzapine), tri- and tetracyclic antidepressants, mianserine, lithium or H2
3. History or presence of sleep disturbances caused by sleep apnea syndrome, narcolepsy, myoclonus epilepsy either observed during polysomnography or explored in patient history. -blockers (e.g. cimetidine), or due to withdrawal from drugs such as anticonvulsants, benzodiazepines, barbiturates, and other hypnotics. 4. Any disorder whose symptoms could overlap those of RLS (mimics of RLS) according to the table of differential diagnoses (see Appendix 12.15).
5. Subjects with acute, clinical augmentation according to MPI criteria checklist previous treatment (Appendix 12.13) and screening tool for augmentation Visit 1 (Appendix 12.11) as assessed by the investigator.
6. Dementia (e.g. Alzheimer’s disease), progressive supranuclear paresis, multisystem atrophy, Huntington’s Chorea, amyotrophic lateral sclerosis, Isaac’s syndrome, Stiff-Man syndrome, or Gilles de la Tourette’s syndrome.
7. History or presence of hallucinating or psychotic episodes which had needed treatment (including schizophrenia).
8. Prohibited concomitant or prior medication: Use of drugs likely to influence sleep architecture or motor manifestations during sleep or other central nervous system (CNS) depressants are not permitted from last week before randomisation visit (Visit 3) onwards. These include levodopa, dopamine agonists, catechol-O-methyl-transferase (COMT) inhibitors, neuroleptics, hypnotics, anxiolytic drugs, benzodiazepines, antidepressants psychostimulatory drugs and anticonvulsants. Inclusion is possible: If patients are on stable therapy for depression or anxiety disorders with antidepressants (SSRI or NARI) or anxiolytic drugs for at least six months.
9. Subjects presently taking, or who have taken naloxone or naltrexone within 30 days of study entry (defined as the start of the Screening Period).
10. Subjects with any contraindication or any history of hypersensitivity to oxycodone, naloxone, related products or other ingredients (severe respiratory depression with hypoxia and/or hypercapnia, severe chronic obstructive lung disease, cor pulmonale, severe bronchial asthma, paralytic ileus).
11. Evidence of clinically significant cardiovascular, renal, hepatic, somatisation disorders or psychiatric disease, as determined by medical history, clinical laboratory tests, ECG results, and physical examination, that would place the subject at risk upon exposure to the study medication or that may confound the analysis and/or interpretation of the study results.
12. Subjects with evidence of impaired liver/kidney function upon entry into the study defined as aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), or alkaline phosphatase levels > 3 times the upper limit of normal; gamma glutamyl transpeptidase (GGT or GGTP) > 3 times the upper limit of normal; total bilirubin level outside of the reference range; and/or creatinine level outside of the reference range (subjects whose total bilirubin levels or creatinine levels are below the lower limit of normal can participate in the study if they meet the criteria described in section 9.4.4.3), or in the investigator’s opinion, liver and/or kidney impairment to the extent that the subject should not participate in this study.
13. Subjects with active alcohol or drug abuse and/or history of opioid abuse.
14. Subjects with a positive urine drug test at screening visit 1, which indicates unreported illicit drug use or unreported use of a concomitant medication not required to treat the subjects’ medical condition(s).
15. Subjects who have received a new chemical entity or an experimental drug within 30 days of study entry (defined as the start of the Screening Period).
16. Serum ferritin below 30 μg/L at Visit 1.
17. Subjects who are pursuing shift-work or who are subject to other continuous non-disease-related life conditions, which do not allow regular sleep at night.
18. Subjects presently taking or who have taken monoamine oxidase inhibitors (MAOI) ≤ 2 weeks prior to the start of the Screening Period. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change in severity of RLS as measured by the IRLS scale total score from end of Maintenance Phase to baseline.
Open Label Extension Phase:
Proportion of subjects with Augmentation according to the MPI Criteria, 2007 (Max Planck Institute Consensus conference) during OXN PR treatment(Expert’s/Investigator’s assessment). Assessment of severity of augmentation (ASRS) during OXN PR treatment. Tolerability and safety of long-term treatment with OXN PR. Long-term efficacy of OXN PR during the open-label Extension Phase in all efficacy variables listed above.
|
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| first phase: double blind; second phase: open label OXN PR only |
|
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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