| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects will have idiopathic Parkinson's disease and be suffering from severe PD associated pain. |
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| E.1.1.1 | Medical condition in easily understood language |
| Severe pain associated with Parkinson's disease |
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| 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 | LLT |
| E.1.2 | Classification code | 10013113 |
| E.1.2 | Term | Disease Parkinson's |
| E.1.2 | System Organ Class | 100000004852 |
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| 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 |
| To demonstrate superiority of OXN PR compared to placebo with respect to analgesic efficacy in subjects with chronic severe pain associated with Parkinson's disease (PD), as assessed by averaged 24 hour pain scores collected for 7 days prior to the clinic visits. |
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| E.2.2 | Secondary objectives of the trial |
| - To demonstrate improvement in the subject's condition, relative to baseline, as measured on the Clinical Global Impression – Improvement scale (CGI-I) and separately the Patient Global Impression – Improvement scale (PGI-I) - To assess the effect of OXN PR on motor symptoms of PD - To assess the effect of OXN PR on non-motor symptoms of PD - To assess the effect of OXN PR on dyskinesia - To assess the effect of OXN PR on sleep - To assess the effect of OXN PR on Quality of Life - To assess the tolerability of OXN PR - To assess the frequency of rescue medication intake |
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| 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 |
| Pharmacogenomic sub-study: Under a separate informed consent process, subjects will be invited to consent to blood sampling for pharmacogenomic testing. The collected blood samples will be anonymised and stored for future analysis. The consent to pharmacogenomic sampling is completely separate from the main study and subjects will be able to take part in the main study without consenting to pharmacogenomic blood sampling. Blood sampling must take place prior to receiving any dose of study medication. Pharmacogenomic samples will be stored at the Clinical Laboratory to provide a resource for future studies to investigate the influence of genetics on response to drugs. Variants in genes of drug targets (such as the opioid receptors) or genes involved in signalling pathways may affect drug efficacy. Similarly, variations in genes involved in the metabolism of compounds (e.g. Cytochrome P450 2D6), may have an influence on the bioavailability of compounds which could lead to increased side effects, or alteration of drug efficacy. Some drugs may therefore be more effective in certain subject groups, or may cause more side effects in certain subjects, depending on genetic makeup. All pharmacogenomic samples will be used by the Sponsor or designees and research will be monitored and reviewed by a committee of scientists and clinicians. |
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| E.3 | Principal inclusion criteria |
| Screening/Double-Blind Phase Inclusion Criteria: 1. Males and females, age of 25 years or over 2. Able to provide written informed consent 3. Primary diagnosis of Parkinson's disease diagnosed by an expert as determined by the UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria (1992) 4. Parkinson's disease Stage II-IV (Hoehn & Yahr staging system) 5. Severe pain graded in at least 1 of the sub sections of the Chaudhuri and Schapira (2009) pain classification system 6. An average pain score of 6 or above on an 11 point NRS, over the previous 7 days determined using diary scores of averaged 24 hour pain in the 7 days leading up to Randomisation (assessed at Visit 2) 7. Female subjects less than one year post-menopausal must have a negative serum or urine pregnancy test recorded prior to the first dose of study medication, be non-lactating, and willing to use an adequate and highly effective method 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 sterilisation, implants, injectables, combined oral contraceptives, some IUDs (hormonal), sexual abstinence or vasectomised partner. Subjects who have had a hysterectomy, sterilisation or who the Investigator is certain to be post-menopausal (e.g. are elderly) do not need to be tested. 8. Subjects who, based on the Investigators' judgement, are likely to benefit from WHO step III opioid therapy for the duration of the study 9. Subjects must not have received opioid containing medication in the last 6 months on a regular basis (i.e. prescribed medication or more than occasional self medication use for cough, cold etc.) 10. Receiving stable treatment for Parkinson's disease for at least 4 weeks prior to randomisation, the dose of which is expected to remain consistent throughout the Double-Blind Phase 11. In the Investigator's opinion, the subject does not have visual or auditory impairments that would reduce their ability to complete study questionnaires or be unable to receive instructions for these 12. Concomitant medication (including co-analgesic) use anticipated to remain stable throughout the Double-Blind Phase of the study 13. Subjects willing and able to participate in all aspects of the study and comply with the use of study medication. Open-Label Extension Inclusion Criteria: 1. Still meet general inclusion criteria for Double-Blind Phase; subjects do not have to meet inclusion 5, 6, 9 & 12 2. Have completed the Double-Blind Phase or discontinued early but have had at least 8 weeks treatment with study medication. |
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| E.4 | Principal exclusion criteria |
| Medical Conditions 1. Cognitive impairment as assessed with the Mini Mental State Examination (MMSE)scoring 24 or less 2. History of psychosis (hallucinations, delusions, etc.) 3. History of drug or alcohol abuse or current compulsive addictive use of drugs or alcohol 4. Parkinsonian-like disease secondary to drug therapy side-effects e.g. due to exposure to medications that deplete dopamine (reserpine, tetrabenazine) or block dopamine receptors (neuroleptics, antiemetics) 5. Parkinson-plus syndromes e.g. progressive supranuclear palsy (PSP) and the multiple system atrophies (MSA) 6. Females who are pregnant (positive β-hCG test) or lactating 7. Any other contraindications to use of the opioid study medication(s) as per the SmPC/IB: - Hypersensitivity to the active substances or to any of the excipients - Any situation where opioids are contraindicated - Severe respiratory depression with hypoxia and/or hypercapnia - Severe chronic obstructive pulmonary disease - Cor pulmonale - Severe bronchial asthma - Non-opioid induced paralytic ileus - Moderate to severe hepatic impairment 8. Any other contraindications to use of the study Double-Blind Phase rescue medication as per the SmPC: - known hypersensitivity to levodopa or benserazide - contra-indicated in narrow-angle glaucoma (it may be used in wide-angle glaucoma provided that the intra-ocular pressure remains under control); severe psychoneuroses or psychoses; severe endocrine, renal, hepatic or cardiac disorders - should not be given in conjunction with, or within 2 weeks of withdrawal of, monoamine oxidase (MAO) inhibitors, except selective MAO-B inhibitors (e.g.selegiline) or selective MAO-A inhibitors (e.g. moclobemide) unless selective MAO inhibitors are given in combination in which case it is contraindicated - not be used in persons who have a history of, or who may be suffering from, a malignant melanoma 9. Subjects with any of the following 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: - myxoedema - untreated hypothyroidism - Addison`s disease - increase of intracranial pressure - uncontrolled seizures or convulsive disorder - evidence of clinically significant cardiovascular, renal, hepatic, gastrointestinal (e.g. paralytic ileus), or psychiatric disease (subjects with controlled co-morbidities may be included following agreement with the Medical Monitor) Contraindicated Treatments 10. Treatment with Deep Brain Stimulation 11. Subjects receiving hypnotics or other central nervous system (CNS) depressants that, in the Investigator's opinion, may pose a risk of additional CNS depression with opioids study medication 12. Subjects presently taking, or who have taken, naloxone or naltrexone ≥ 30 days prior to the Screening Visit 13. Subjects who have received an investigational medicinal product within 30 days of study entry (defined as the start of the Screening Phase) 14. Any current use of an opioid other than the study medication provided 15. 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) 16. Abnormal parameters as defined: - aspartate aminotransferase (AST; SGOT) > 3 times the upper limit of normal - alanine aminotransferase (ALT; SGPT) > 3 times the upper limit of normal - alkaline phosphatase levels > 3 times the upper limit of normal - gamma glutamyl transpeptidase (GGT or GGTP) > 3 times the upper limit of normal - Abnormal total bilirubin and/or creatinine level(s) > 1.5 times the upper limit of normal. 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 below: Bilirubin as well as creatinine values below the lower limit of normal are not necessarily a criterion for an impairment of organ function. Therefore values out of the lower normal range do not automatically lead to an exclusion of the subject from the study. The decision to exclude/discontinue a subject from the study due to bilirubin as well as creatinine levels below the lower limit of normal should be based on the medical judgment of the Investigator and based on the presence or absence of pathophysiological impairment of the respective organs. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for the primary comparison of OXN PR vs. placebo: - Averaged 24 hour pain scores collected for 7 days preceding the study clinic visit at week 16. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Evaluation after study end. No interim analysis planned |
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| E.5.2 | Secondary end point(s) |
| The following key secondary endpoints for the primary comparison of OXN PR vs. placebo will be tested in a hierarchical testing strategy: - Averaged 24 hour pain scores collected for the 7 days preceding individual clinic visits during the Double Blind Phase - Percentage of responders (defined as a ≥30% reduction from baseline) in averaged 24 hour pain scores collected for 7 days preceding the study clinic visit at week 16 - CGI-I: Percentage of responders (defined as a response of 'Much improved' or 'Very much improved') on the CGI-I scale (as defined by the Investigator) Other exploratory endpoints: - Percentage of responders (defined as a response of 'Much improved' or 'Very much improved') on the PGI-I scale (as defined by the subject) - Change from baseline in the total score and domains of the Non Motor Symptom Assessment Scale for Parkinson's Disease to the end of the Double Blind Phase (week 16) - Change from baseline in the total score of the UPDRS Part III/IV Motor Examination to the end of the Double Blind Phase (week 16) - Change from baseline in percentage of subjects meeting wearing off criteria (defined as the presence of at least one symptom in the WOQ9 with improvement after the next dose of anti Parkinsonian medication) - Change from baseline in the total score of the CISI PD to the end of the Double Blind Phase (week 16) - Frequency of rescue medication use during the Double Blind Phase - Change from baseline in the total score of the PDSS2 to the end of the Double Blind Phase (week 16) - Change from baseline in the total score of the PDQ8 to the end of the Double Blind Phase (week 16) - Change from baseline in EQ5D index score to the end of the Double Blind Phase (week 16) - Change from baseline in the anxiety domain score of the HADS to the end of the Double Blind Phase (week 16) - Change from baseline in the depression domain score of the HADS to the end of the Double Blind Phase (week 16) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Evaluation after study end. No interim analysis planned |
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| 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 | Yes |
| 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 | 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | 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
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| Last visit of last subject. |
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| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 10 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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