| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe chronic non-cancer or cancer pain with opioid induced constipation |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033371 |
| E.1.2 | Term | Pain |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010774 |
| E.1.2 | Term | Constipation |
|
| 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 objectives are to investigate whether a hydromorphone/naloxone combination will lead to comparable analgesia (using NRS pain) with a decrease in constipation (BFI) in patients with moderate to severe chronic non-cancer or cancer pain suffering from constipation caused or aggravated by opioids when compared with hydromorphone alone and to investigate the optimal dose ratio of hydromorphone and naloxone based on findings of the pain and bowel assessments and safety data |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to assess the frequency of rescue medication use, to assess the incidence/frequency of laxative use, to assess aspects of constipation [Complete Spontaneous Bowel Movement (CSBMs)]. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects at least 18 years (females less than one year post-menopausal must have a negative serum or urine pregnancy test 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 sterilisation, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or vasoectomised partner).
2. Subjects who are receiving WHO step II or step III analgesic medication for the treatment of non-cancer or cancer pain.
3. Documented history of non-cancer or cancer pain that requires opioid therapy (8, 24 or 48 mg hydromorphone PR per day for the duration of the study).
4. Subjects with constipation caused or aggravated by opioids:
• 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.
• In the opinion of the subject and Investigator it is confirmed that the subject’s constipation is induced, or worsened by the subject’s pre study opioid medication (present at Screening)
5. Subjects must be willing to discontinue their current opioid analgesic routine.
6. Subjects must be willing to discontinue their current laxative regimen and willing to comply with the use of oral bisacodyl as laxative rescue medication.
7. Subjects taking daily fiber supplementation or bulking agents are eligible if they can be maintained on a stable dose and regimen throughout the study, and in the Investigator’s opinion are willing and able to maintain adequate hydration.
8. Subjects must be willing and able (e.g. mental and 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, and compliance with protocol requirements as evidenced by providing written, informed consent.
9. In the Investigator’s opinion the subject’s non-analgesic concomitant medications, including those medications for the treatment of depression are thought to be stable, and will remain stable throughout the Double-blind Phase of the study.
10. In the Investigator’s opinion the non opioid analgesic medication dose will remain stable during the Double-blind Phase. |
|
| E.4 | Principal exclusion criteria |
1. Any history of hypersensitivity to hydromorphone, naloxone, bisacodyl, related products or other ingredients of the study medication.
2. Any contraindication to hydromorphone, naloxone, bisacodyl, related products and other ingredients of the study medication.
3. Active alcohol or drug abuse and/or history of opioid abuse.
4. Evidence of clinically significant cardiovascular, renal, hepatic, gastrointestinal (e.g. paralytic ileus), 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.
5. Chronic or intermittent pain that results from Fibromyalgia or Rheumatoid Arthritis. 6. 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 opioid study medication.
7. Subjects with uncontrolled seizures or convulsive disorder.
8. Surgery within 2 months prior to the start of the Screening Period, or planned surgery during the 8-week Maintenance Phase that may affect GI motility or pain.
9. Subjects presently taking, or who have taken, naloxone <=30 days prior to the start of the Screening Period.
10. Subjects suffering from diarrhoea.
11. Subjects with any situation in which opioids are contraindicated (e.g., severe respiratory depression with hypoxia and/or hypercapnia, severe chronic obstructive lung disease, paralytic ileus).
12. Subjects with hypothyroidism, Addison`s disease, increase of intracranial pressure.
13. Abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), or alkaline phosphatase levels (> 3 times the upper limit of normal)
14. Abnormal total bilirubin and/or creatinine level(s) (greater than 1.5 times the upper limit of normal), gamma glutamyl transpeptidase (GGT or GGTP) ≥ 5 times the upper limit of normal. Exclusion criteria for subjects suffering from non-cancer pain: 15. 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).
Exclusion criteria for subjects suffering from cancer/cancer pain:
16. 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.
17. Cyclic chemotherapy in the two weeks before the screening visit or planned during the study that has shown in the past to significantly influence bowel function. If subjects are having their first cycle of chemotherapy during the 2 weeks before the screening visit or during the study they should be excluded from the study.
18. Radiotherapy that, in the Investigators opinion, would influence bowel function or pain during the study.
19. 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). Concurrent enrolment in another clinical trial is not permitted unless the sole purpose of the other trial at the time of HMX3501 screening is for long-term survival data. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Appropriate Hydromorphone Prolonged Release:naloxone (HM PR:naloxone) ratio, defined as
• Non-inferior analgesic efficacy compared to the HM PR:naloxone placebo group and
• Superior bowel function based on the Bowel Function Index value compared to the HM PR:naloxone placebo group
• Bowel Function Index: Summary statistics for the mean bowel function index during the last 7 days will be provided at each study visit for the different dose ratios of hydromorphone and naloxone, for the different hydromorphone/naloxone doses as well as for the absolute doses of naloxone.
To test for difference comparing the dose ratios of hydromorphone/naloxone with hydromorphone/naloxone placebo, t-tests will be performed for the change from randomisation (V3) to end of Double-blind Phase (V10). In addition, two-sided 95% CIs for the difference between the ratios and hydromorphone/naloxone placebo will be provided. An exploratory response surface analysis will also be performed for the change from randomisation (V3) to end of Double-blind Phase (V10). This analysis should give further information about the intermediate hydromorphone dose strengths for the investigated dose ratios. These analyses will be performed for the FULL-ANALYSIS and Per Protocol (PP) populations. In order to keep a multiple significance level of 5% per efficacy variable the various hydromorphone : naloxone ratios will be assessed in decreasing order by means of a sequentially rejective test procedure. A ratio group will be tested only if any higher ratio were previously assessed superior to the placebo group. Therewith only those ratio groups will be considered which have been previously shown to be non-inferior to the naloxone placebo group in the pain intensity score.
Pain Intensity: Summary statistics for mean average 24 hrs pain will be provided at each study visit for the different dose ratios of hydromorphone and naloxone, for the different hydromorphone doses as well as for the absolute doses of naloxone. To test for non-inferiority, one-sided t-tests at a 5% significance level will be performed for averaged Double-blind Phase pain score from first post-randomisation visit (V4) to end of Double-blind Phase (V10) with a non-inferiority bound of 20% difference on a NRS of 0 -10. In addition, two-sided 90% confidence intervals (CI) for the difference between the ratios and hydromorphone /naloxone placebo will be provided. An exploratory response surface analysis will also be performed for the change from randomisation (V3) to end of Double-blind Phase (V10). This analysis should give further information about the intermediate hydromorphone dose strengths for the investigated dose ratios. These analyses will be performed for the FULL-ANALYSIS and PP populations. In order to keep a multiple significance level of 5% per efficacy variable the various hydromorphone : naloxone ratios will be assessed in an increasing order by means of a sequentially rejective test procedure. A ratio group will be tested only if any lower ratio group were previously assessed to be non-inferior to the placebo group. |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 5 |
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