| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024891 |
| E.1.2 | Term | Low back pain |
| E.1.2 | System Organ Class | 100000004859 |
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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 evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl fixed combination versus placebo in moderate to severe acute low back pain after the first dose (first 8 hours). |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl fixed combination versus TRAM.HCL 100 mg in moderate to severe acute low back pain after the first dose (first 8 hours).
To evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl fixed combination in moderate to severe acute low back pain versus TRAM.HCl 100 mg after multiple doses (from t8h until day 5).
To assess the safety and tolerability of DKP.TRIS/TRAM.HCl fixed combination after single and multiple doses.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Properly executed written informed consent.
2. Male or female patients aged 18 years to 65 years.
3. Patients with acute low back reporting pain of at least moderate intensity at Screening (NRS score ≥ 5). The onset of the current acute low back pain episode is within 48 hours prior to Screening.
4. Patients with or without radiculopathy will be included, excluding those with neurological signs, according to the Quebec Task Force classification.
5. Naïve patients to any low back pain or patients with previous history of low back pain experiencing a new episode, preceded by a period of at least 2 months without any low back pain prior to Screening.
6. Patients free from analgesic (as per exclusion criterion 14) due to previously administered pain killer (immediate or slow release formulations), according to physician’s judgment.
7. Females participating in the study must be either:
- Females of nonchildbearing potential, defined as any woman who had undergone surgical sterilization (documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or is more than 2 years postmenopausal (defined as no menses for 12 months);
- Females of childbearing potential (following menarche until menopause unless permanently sterile) provided that they have a negative pregnancy test at Screening and are routinely using an effective method of birth control resulting in a low failure rate (ie, combined hormonal contraception, intrauterine device, condoms in combination with a spermicidal cream, male partner sterilization (vasectomy), bilateral tubal occlusion or total sexual abstinence) during the study treatment.
8. Mentally competent and able to understand and give written informed consent prior to Screening.
9. Compliant to undergo all visits and procedures scheduled in the Study. |
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| E.4 | Principal exclusion criteria |
1. Patients who are judged by the Investigator not to be suitable candidates for the study treatments and the RM based on their medical history, physical examination, CM and concurrent systemic diseases.
2. Clinically significant abnormalities in the vital signs as per Investigator’s judgment.
3. Patients with acute low back pain and radiation to limb with presence of neurologic signs (focal weakness, asymmetry of reflexes, sensory loss in a dermatome, or loss of bowel, bladder, or sexual function) according to Quebec Task Force Classification.
4. History of hypersensitivity to the study treatments, RM or to any other nonsteroidal anti-inflammatory drugs (NSAIDs), or opioids.
5. Known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates.
6. History of peptic ulcer, gastrointestinal disorders when taking NSAIDs, gastrointestinal bleeding, or other active bleeding.
7. History of allergy (eg, precipitate attacks of asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria or angioneurotic oedema) to the study treatments, RM or to any other NSAIDs, or opioids.
8. Anamnestic mild to severe renal dysfunction, mild to severe hepatic dysfunction, as per Investigator’s judgment.
9. Patients with chronic dyspepsia.
10. Patients with severe heart failure (Class III and Class IV of New York Heart Association [NYHA] Classification).
11. History of hemorrhagic diathesis and other coagulation disorders.
12. History of or current epilepsy or convulsions.
13. Patients with Crohn’s disease or ulcerative colitis.
14. Patients receiving monoamine oxidase (MAO) inhibitors (a minimum of 14 days of washout must elapse prior to the Screening).
15. Treatment with topical preparations/medications within 4 hours prior to Screening, anesthetics and muscle relaxants within 8 hours prior to Screening, short-acting analgesics (eg, paracetamol) within 4 hours prior to Screening, other analgesics within 5 half-lives prior to Screening or use of an opioid within the 14 days preceding Screening.
16. Treatment with high doses of salicylates (≥3 g/day), anticoagulants, thrombolytic and antiplatelet agents, heparins, corticosteroids (except inhalers and topical agents), lithium methotrexate, used at high doses of 15 mg/week or more, hydantoins (including phenytoin) and sulphonamides, antiepileptics, antipsychotics, serotonin reuptake inhibitors and tricyclic antidepressants, and analgesics within 48 hours or 5 half-lives (whichever is the longer) prior to Screening.
17. Patients using sedatives (eg, benzodiazepines) and hypnotic agents within 8 hours before Screening.
18. Any chronic or acute painful condition other than the study indication that may interfere with the assessment of the efficacy of the study treatment.
19. Any non-pharmacological interventional therapy for low back pain (physical therapy, acupuncture, massage etc.) one month before Screening.
20. Patients with litigation related to work.
21. Patients with severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake) within one month prior to Screening.
22. Severe respiratory depression according to physician’s judgment.
23. Participation in other clinical studies in the previous 4 weeks.
24. History of drug or alcohol abuse. For the purpose of the study, alcohol abuse is defined as regularly intake of more than 4 units of alcohol per day (1 unit corresponds approximately to 125 ml wine, 200 ml beer, 25 ml spirit).
25. History of any illness or condition that, in the opinion of the Investigator might pose a risk to the patient or confound the efficacy and safety results of the study.
26. Pregnant and breastfeeding women. NOTE: a pregnancy test will be performed on all women of childbearing potential at Screening.
27. Patients presenting any of the contraindications reported for dexketoprofen/tramadol, tramadol or paracetamol (according to the SmPC).
28. Known or suspected serious spinal pathology (eg, metastatic, inflammatory or infective diseases of the spine, cauda equine syndrome, trauma, spinal fracture).
29. Spinal surgery within the preceding 6 months. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time to first achieve a numeric rating scale-pain intensity (NRS-PI) score of <4 or a pain intensity reduction ≥30% |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From drug intake till 8 hours after the first dose (t8h). |
|
| E.5.2 | Secondary end point(s) |
Efficacy after the first dose (first 8 hours):
1. Pain Relief (PAR) – verbal rating scale (VRS) scores at each prespecified time point
2. Total pain relief (TOTPAR)
3. Percentage of maximum TOTPAR (% max TOTPAR)
4. Percentage of subjects achieving at least 50% of maximum TOTPAR
5. Mean Pain Intensity (PI) - visual analogue scale (VAS) scores at each prespecified time point
6. Summed pain intensity difference (SPID)
7. Percentage of maximum SPID (% max SPID)
8. Percentage of subjects achieving at least 30% of PI reduction versus baseline
9. Patient global evaluation (PGE) of the study medication
10. Time to rescue medication (RM)
11. Percentage of patients who required RM
Efficacy after multiple doses (5 days multiple doses):
1. Pain relief (PAR) – verbal rating scale (VRS) scores at each prespecified time point
2. Total pain relief (TOTPAR)
3. Percentage of maximum TOTPAR (% max TOTPAR)
4. Percentage of subjects achieving at least 50% of maximum TOTPAR
5. Pain Intensity (PI) - visual analogue scale (VAS) scores at each prespecified time point
6. Summed pain intensity difference (SPID)
7. Percentage of maximum SPID (% max SPID)
8. Percentage of subjects achieving at least 30% of PI reduction versus baseline
9. Patient global evaluation (PGE)
10. Percentage of subjects who required rescue medication (RM)
11. Roland Morris Disability Questionnaire (RMQ)
12. Treatment Satisfaction Questionnaire for Medication (TSQM)
Complete treatment and assessment period:
1. Time to first achieve an NRS score <4 or a pain intensity reduction of ≥30%, excluding subjects assigned to the placebo treatment arms during the single-dose phase
2. TOTPAR, excluding subjects assigned to the placebo treatment arms during the single-dose phase
3. SPID, excluding subjects assigned to the placebo treatment arms during the single-dose phase
4. Time to RM, excluding subjects assigned to the placebo treatment arms during the single-dose phase
Safety after single and multiple doses:
1.Incidence, intensity (severity), seriousness and treatment causality of treatment-emergent AEs
2.Frequency of clinically significant changes in clinical laboratory evaluations, physical examination, and vital signs post-dose versus baseline. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy after the first dose (first 8h):
1,5. over the 8 hours after first dose
2,3,4,6,7,8,11. at 4, 6, and 8 hours after first dose
9. at 8 hours after first dose
10. from baseline till 8 hours after first dose
Efficacy after multiple doses (5 days multiple doses):
1,5. over multiple-dose phase
2,3,4,6,7,8,10. at 24, 48, 72, and 96 hours of multiple-dose phase
9,11,12. at 96 hours of multiple-dose phase
Complete treatment and assessment period:
1,4. from the first drug intake till 5 days after the first dose
2,3. at 104 hours from the first drug intake till 5 days after the first dose
Safety after single and multiple doses:
1. from first drug intake
2. post-dose versus baseline |
|
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 20 |
| 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
|
| last visit of the last subject (LVLS) |
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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