Determine the Safety and Efficacy of Oxy/Nal Tablets Compared to Oxy PR in Subjects With Cancer Pain

Study Overview
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Brief Summary
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To Determine the Safety and Efficacy of Oxycodone / Naloxone Prolonged Release Tablets compared to Oxycodone PR in Subjects with Moderate to Severe, Chronic Cancer Pain

Detailed Description
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This is a randomised, double-blind, double-dummy, parallel group study using OXN and OXY PR to treat moderate to severe, chronic cancer pain. Subjects with documented history of cancer pain that requires around the clock opioid therapy will be included. Subjects must have a medical history of constipation that was induced by, or worsened by their opioid therapy.

Official Title
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A Phase III, Randomized, Double-blind, Double-dummy, Parallel Group Study to Determine the Safety and Efficacy of Oxy/Nal Prolonged Release Tablets Compared to Oxy PR in Subjects With Moderate to Severe, Chronic Cancer Pain

Conditions
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Cancer, Pain

Intervention / Treatment
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* Drug: Oxycodone/Naloxone
* Drug: Oxycodone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Males & females, at least 18 years or older with a diagnosis of cancer. Females less than one year post-menopausal must have a negative urine pregnancy test recorded prior to the first dose of study medication, be non-lactating, & willing to use adequate & highly effective method of contraception throughout the study. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently correctly such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (hormonal), sexual abstinence or vasectomised partner. Subjects who are receiving WHO step II or Step III analgesic medication who have constipation induced, or worsened by their opioid medication, as shown by the subject's medical need of regular intake of laxatives to have at least 3 bowel evacuations per week, or having less than 3 bowel evacuations when not taking a laxative, respectively. the subject's self-assessment that their constipation was induced or worsened by their current pre-study opioid medication. Documented history of moderate to severe, chronic cancer pain that requires around the-clock opioid therapy (starting dose of oxycodone PR between 20-80 mg/day) & are likely to benefit from WHO step III opioid therapy for the duration of the study. Subjects must be willing to discontinue their current opioid analgesic routine. Opioid medication continue at a stable or nearly stable dose in the investigator's opinion during the treatment. Subjects are willing to discontinue pre study laxative medication & take study specific laxative medication. Subjects taking daily fibre supplementation or bulking agents are eligible if they can be maintained on a stable dose & regimen throughout the study, & in the investigators opinion are willing & able to maintain adequate hydration. Subjects willing & able (e.g. mental & physical condition) to participate in all aspects of the study, including use of medication, completion of subjective evaluations, attending scheduled clinic visits, completing telephone contacts, & compliance with protocol requirements as evidenced by providing written, informed consent. Subjects already taking non-opioid analgesics & all other concomitant medications (including those for the treatment of depression) are eligible to take part in the study. However, all concomitant medications that are considered necessary for the subject's welfare should be continued at a stable dose throughout the double-blind phase of the study & under the supervision of the investigator. Expected survival time > 3 months. With capability of reading, understanding & signing inform consent form & compliance with protocol requirements. Exclusion Criteria Subjects that require a dose >80 mg/day oxycodone PR at the start of the double-blind phase. Any history of hypersensitivity to oxycodone, naloxone, morphine, bisacodyl, related products & other ingredients. Subjects with any situation in which opioids are contra-indicated, severe respiratory depression with hypoxia & or hypercapnia, severe chronic obstructive pulmonary disease, cor pulmonal, severe bronchial asthma, paralytic ileus. Subjects with evidence of clinically significant gastrointestinal disease (e.g. paralytic ileus, peritoneal carcinosis), significant structural abnormalities of the gastrointestinal tract (e.g. scarring, obstruction etc) either related or not related to the underlying cancer or disease progression. Evidence of clinically significant cardiovascular, renal, hepatic or psychiatric disease, as determined by medical history, clinical laboratory tests, ECG results & physical examination, that would place the subject at risk upon exposure to the study medication or that may confound the analysis & or interpretation of the study results. Abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), r-glutamyltransferase (GGT) or alkaline phosphatase levels (>3 times the upper limit of normal) or an abnormal total bilirubin & or creatinine level(s) (greater than 1.5 times the upper limit of normal). Cyclic chemotherapy in the two weeks before the screening visit or planned during the core study that has shown in the past to influence bowel function. If subjects are having their first cycle of chemotherapy during the 2 weeks before the screening visit or during the double-blind phase of the study they should be excluded from the study. Radiotherapy that, in the investigators opinion, would influence bowel function or pain during the double-blind phase of the study. Subjects with known or suspected unstable brain metastases or spinal cord compression that may require changes in steroid treatment throughout the duration of the study. Subjects with uncontrolled seizures. Subjects with increased intracranial pressure. In the investigator's opinion, subjects who are receiving hypnotics or other central nervous system (CNS) depressants that may pose a risk of additional CNS depression with opioid study medication. Subjects with myxoedema, not adequately treated hypothyroidism or Addisons disease. Subjects who have a confirmed diagnosis of ongoing irritable bowel syndrome(IBS). Surgery completed within 4 weeks prior to the start of the Screening Period, or planned surgery during the study that would influence pain or bowel function during the study or preclude completion of the study. Subjects receiving opioid substitution therapy for opioid addiction (e.g. methadone or buprenorphine). Active alcohol or drug abuse & or history of opioid abuse. Subjects suffering from diarrhoea & or opioid withdrawal. Subjects presently taking, or who have taken, naloxone ≤30 days prior to the start of the Screening Period. Subjects who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days of study entry (defined as the start of the Screening Period), unless the subject is on data collection phase for Overall Survival.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oxycodone/Naloxone<br>5/2.5mg, 10/5mg, 20/10mg or 40/20mg | Drug: Oxycodone/Naloxone<br> <br> * Other names: Targin;|
| Active Comparator: Oxycodone<br>5mg, 10mg, 20mg or 40mg | Drug: Oxycodone<br> <br> * Other names: OXY PR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change of BFI-Bowel Function Index at visit8 | BFI is the mean of NAS for the following items: Ease of defecation Feeling of incomplete bowel evacuation. Personal judgment of constipation. NAS was a measure of 0-100 where 0 was easy/no difficulty/not at all and 100 was severe difficulty/very strong,total score range is 0-300.Do higher values represent a worse outcome. | Visit8, visit8 taking place at week 4 or after early discontinuation/withdrawal from study | 
| The Change of BPI-SF at visit8 | Brief pain inventory short-form(BPI-SF) recorded at final visit assesses subject's average pain over the last 24 hours. score range is 0(no pain)-10(pain as bad as you can imagine).Do higher values represent a worse outcome. | Visit8, visit8 taking place at week 4 or after early discontinuation/withdrawal from study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change of Symptoms of Constipation Based on Laxative Use From visit5 to visit8 | At Visit 5(day7) and visit8(day28) number of bisacodyl taken(Number of laxative tablets took during the last 7 days (per week) and Daily number of laxative tablets took during the last 7 days (per day)*) for OXN PR and OXY PR groups. | visit 5 (week 1) to visit8 (week 4 or early discontinue/withdrawal from study) | 
| The Change of Rescue Medication Use From visit5 to visit8 | The average daily dose of rescue medication (Morphine Sulfate Tablet) for OXN PR group and OXY PR group at Visit 5(first week of double blind) and at Visit 8(last week of double blind). | visit 5 (week 1) to visit8 (week 4 or early discontinue/withdrawal from study) | 
| The Change of Modified Subjective Opiate Withdrawal Scale (SOWS) From Visit1 to visit3,visit1 to visit9 | to compare the Modified SOWS's Change from Visit 1(day-10-0) to Visit 3(day1),Change from Visit 1 to Visit 9(day35).The SOWS was scored as the total of the 15 symptoms. each symptoms score is 0(not at all)-4(extremely).total score range is 0-60.Do higher values represent a better outcome. | Visit1(screening visit) to visit3 (day 1), visit1(screening visit) to visit9 (week 5) | 
| To Assess Quality of Life Based on EQ-5D | To assess quality of life based on EQ-5D by subjects evaluation via patient dairy.the quality of life based on EQ-5D at Visit1 (day-10-0) and end of treatment Visit8(day28). The scarc range is 0(the best state you can imagine)-100(the worst state you can imagine).Do higher values represent a worse outcome. | Visit1(screening visit) to Visit8 (week 4 or after early discontinuation/withdrawal from study) | 
| The Change of Individual Items in BPI-SF(Except for Pain in Average) by Visit | To compare the change of Brief pain inventory short-form (BPI-SF) 11 indivial items (except for pain in average) at visit2(day0) ,visit5(day7),visit6(day14),visit7(day21), visit8(day28). each item range (except for how much relief from treatment /medication last 24hours is 0-100%,do higher values represent a better outcome.) is 0-10, do higher values represent a worse outcome. | visit2 (day 0) to visit8 (week 4 or early discontinue/withdrawal from study) | 
| The Change of Bowel Movement by Visit | Number pf bowel movements(BM) and number of days the subjects had a bowel movement in the last 7 days before the study visit will be summarized at visit2(day0) ,visit5(day7),visit6(day14),visit7(day21), visit8(day28).. | visit2 (day 0) to visit8 (week 4 or early discontinue/withdrawal from study) | 
| The Chage of Symptoms of Constipation Based on Laxative Use From visit5 to visit8 | At Visit5(day7) and visit8(day28) number of bisacodyl taken(Number of laxative tablets took during the last 7 days (per week) and Daily number of laxative tablets took during the last 7 days (per day)*) for OXN PR and OXY PR groups | visit 5 taking place at week 1 to visit8 taking place at week 4 or early discontinue/withdrawal from study where applicable |