| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic severe cancer or non-cancer pain |
| kronična huda bolečina rakavega ali nerakavega izvora |
|
| E.1.1.1 | Medical condition in easily understood language |
| Severe chronic pain |
| kronična huda bolečina |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| 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 | 10049475 |
| E.1.2 | Term | Chronic pain |
| E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
|
| 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 that once daily administration of Hydromorphone HCl PR tablets XL is not inferior compared to a twice daily administration of Palladon® retard capsules at the same daily dosage. |
|
| E.2.2 | Secondary objectives of the trial |
• In case of non-inferiority, to demonstrate that once daily administration of Hydromorphone HCl PR tablets XL is more effective (superior) as twice daily administration of Palladon® retard capsules at the same daily dosage.
• To assess the safety and tolerability of once daily administration of Hydromorphone HCl PR tablets XL in comparison with twice daily administration of Palladon® retard capsules.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female patients ≥18 years of age.
2. Patients with chronic severe cancer or non-cancer pain.
3. Patients with predominantly non-neuropathic pain (assessed by the DN4 Neuropathic Pain Diagnostic Questionnaire).
4. Patients with documented history of chronic severe pain that requires around-the-clock opioid therapy and are likely to benefit from WHO step III opioid therapy for the duration of the study.
5. Women of childbearing potential agree to undergo pregnancy tests.
6. Patients 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 visits, completing telephone contacts, and compliance with protocol requirements as evidenced by providing signed written informed consent.
7. For inclusion in double-blind treatment phase adequate analgesia (mean "current" pain intensity per day >0 mm and ≤40 mm on VAS) prior to randomisation for at least three consecutive days.
8. For inclusion in double-blind treatment phase stable analgesic requirements of at least 8 mg hydromorphone HCl per day prior to randomisation for at least three consecutive days (stable maintenance dose of hydromorphone; ≤2 doses of rescue medication per day), tolerable AEs.
|
|
| E.4 | Principal exclusion criteria |
1. Patients with any situation in which opioids are contra-indicated, severe respiratory depression with hypoxia and/or hypercapnia, severe chronic obstructive pulmonary disease, cor pulmonale, severe bronchial asthma, paralytic ileus.
2. Hypersensitivity to hydromorphone or any of the excipients of the study medication.
3. Patients requiring less than 8 mg or more than 32 mg hydromorphone HCl per day at the start of the double-blind treatment phase.
4. Surgery within 1 month prior to study start or anticipated or scheduled surgical intervention during the study.
5. Intravenous chemotherapy or radiotherapy for pain alleviation or neural blockade within 2 weeks prior to study start or anticipated or scheduled during the course of the study.
6. Known or suspected significant hepatic impairment (hepatic transaminases >3 times the upper limit of normal).
7. Known or suspected severe renal impairment (CRCL <30 ml/min) or patients with renal failure who are on any form of dialysis.
8. Known or suspected significant circulatory disturbance, hypotension, or circulatory shock.
9. Known or suspected clinically relevant endocrine disorder, such as myxoedema, not adequately treated hypothyroidism or adrenocortical insufficiency (e.g. Addison's disease).
10. Known or suspected clinically significant bowel disease (e.g. paralytic ileus, significant impairment of bowel motility severe enough to potentially result in ileus, obstructive or inflammatory bowel disease).
11. Known or suspected acute or chronic pancreatitis or biliary tract disease.
12. Any gastro-intestinal pathology or surgery or intractable vomiting likely to significantly influence drug absorption.
13. Inability to swallow the study drugs whole (e.g. due to dysphagia).
14. Known or suspected significant prostatic hypertrophy or urethral stricture severe enough to potentially result in urinary retention.
15. Known or suspected CNS depression (signs/symptoms: decreased vital signs, impaired thinking and perception, slurred speech, slowed reflexes, fatigue, decreased consciousness), coma, or convulsive disorder.
16. Known or suspected elevation of intracranial pressure.
17. Known or suspected acute alcoholism, delirium tremens, or toxic psychosis.
18. History of drug addiction or drug seeking behaviour.
19. Concomitant treatment with MAO inhibitors.
20. Pregnancy or breast-feeding. Women of childbearing potential unable or unwilling to practice adequate contraceptive measures. Reliable methods for women are hormonal contraceptives, surgical intervention (e.g. tubal ligation), intrauterine device (IUD) and sexual abstinence.
21. Any other condition of the patient that in the opinion of the investigator may compromise evaluation of the study treatment or may jeopardize patient's safety (e.g. risk of suicide), compliance or adherence to protocol requirements.
22. Previous enrolment in this study or participation in any other drug investigational trial within the past 30 days (or five half-lives whichever is longer) prior to enrolment.
23. Persons committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| the mean "current" Pain Internsity (PI) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| assessed over all time points (daily evaluations: 08:00 h / 12:00 h / 16:00 h / 20:00 h) of the last 5 treatment days of period 1 and 2 i.e. the "current" PIs at the four scheduled time points and the "current" PIs before administration of rescue medication (= overall "current" PI). |
|
| E.5.2 | Secondary end point(s) |
- the mean "recalled pain during night" for the last 5 treatment days of period 1 and 2
- the mean "recalled pain during day" for the last 5 treatment days of period 1 and 2
- the mean "current" PI, i.e. the "current" PIs at the four scheduled time points and the "current" PIs before administration of rescue medication, for each of the last 5 treatment days of period 1 and 2 (= mean "current" PI per day, e.g. mean "current" PI score on Day 9)
- the mean "current" PI for each of the four scheduled time points over the last 5 treatment days of period 1 and 2 (= mean "current" PI per time point; e.g. mean "current" PI score at 08:00 h)
overall effectiveness: assessed by patients and investigator
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PI will be assessed four times daily (allowed deviation ±30 minutes) during the open-label titration / stabilisation period and during the two double-blind treatment periods at the following time points:
• 08:00 h (before drug intake),
• 12:00 h,
• 16:00 h,
• 20:00 h (before drug intake).
At these time points, patients will rate their "current" PI.
In addition, patient's will rate their "current" PI:
• before administration of any rescue medication.
overall effectiveness: assessed at the end of each treatment period (in the morning on Day 14 and Day 27 |
|
| 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 | 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 | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Czech Republic |
| Germany |
| Poland |
| Romania |
| Serbia |
| Slovakia |
| Slovenia |
|
| 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
|
| The study ends with the last visit of the last patient participating in the trial |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| 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 | 0 |
| 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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