| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The purpose of the trial is to assess the efficacy of Pregabalin Krka (pregabalin) and Dulsevia® (duloxetin) in patients with PDPN, investigate the effect of Pregabalin Krka and Dulsevia® on pain and on quality of life (QOL), depression symptoms, cognitive functions, sleep quality and daytime sleepiness and assess the safety of Pregabalin Krka and Dulsevia® in patients with PDPN. |
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| E.1.1.1 | Medical condition in easily understood language |
| To asses the efficacy of Pregabalin Krka (pregabalin) and Dulsevia® (duloxetin) in patients with painful diabetic peripheral neuropathy |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| 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 purpose of the trial is to assess the efficacy of Pregabalin Krka (pregabalin) and Dulsevia® (duloxetin) in patients with PDPN, investigate the effect of Pregabalin Krka and Dulsevia® on pain and on quality of life (QOL), depression symptoms, cognitive functions, sleep quality and daytime sleepiness and assess the safety of Pregabalin Krka and Dulsevia® in patients with PDPN. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female and male patients aged 18-85 years.
2. Patients with a history of type 2 diabetes mellitus according to The American Diabetes Association (ADA).
3. Patients with a diagnosis of painful diabetic peripheral neuropathy (PDPN) caused by type 2 diabetes mellitus based on Douleur Neuropathique questionnaire (DN4 ≥4).
4. Patients whose average pain intensity in PDPN in last 24 hours (measured by VAS), evaluated on baseline visit, is equal or more than 40 mm (0 mm =’no pain’ and 100 mm =’worst possible pain’).
5. Ability to adhere to trial protocol.
6. Written informed consent. |
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| E.4 | Principal exclusion criteria |
1. Patients who took PDPN medication and/or analgesics on a day of baseline visit.
2. Patients with a known hypersensitivity to duloxetine, pregabalin, paracetamol or tramadol or any of the inactive ingredients or have any contraindication for the use of duloxetine, pregabalin, paracetamol or tramadol.
3. Patients with a history of inadequate pain response (pain reduced was equal or less than 30%) to:
3.1 pregabalin at maximum allowed treatment daily dose 600 mg,
3.2 duloxetine at maximum allowed treatment daily dose 120 mg,
3.3 venlafaxine at maximum allowed treatment daily dose 375 mg,
3.4 gabapentin on daily treatment dose more than 1800 mg
3.5 amitriptilin at maximum allowed treatment daily dose 150 mg.
4. Patients, who are currently treated with a daily dose that exceeds:
4.1 150 mg of pregabalin or
4.2 60 mg of duloxetine or
4.3 150 mg of venlafaxine or
4.4 600 mg of gabapentin.
5. Patients with an uncontrolled type 2 diabetes mellitus
6. The scores of less than 20 on Montreal cognitive assessment (MoCA).
7. Have any other type of neuropatic pain, contrasted to PDPN.
8. Evidence of another cause of distal polyneuropathy other than diabetic.
9. Have a serious (evaluated by physician) unstable cardiovascular (e.g. uncontrolled hypertension), hepatic, renal, respiratory, ophthalmologic, gastrointestinal, or hematologic illness, symptomatic peripheral vascular disease, malignant disease or other medical condition that could lead to hospitalisation during the course of the trial.
10. Have a diagnosis or history of uncontrolled glaucoma.
11. Known or suspected alcohol or drug abuse or addiction (excluding nicotine and caffeine).
12. Patients with any prior history of depression (less than one year after completing the last medical treatment), mania, bipolar disorder, psychosis or schizophrenia.
13. Pregnancy, lactation and women of child-bearing potential without highly effective* or at least acceptable** contraception (according to the Recommendations related to contraception and pregnancy testing in clinical trials).
14. Patients with a history of epilepsy, stroke or neurodegenerative disease.
15. Patients taking Monoamine oxidase (MAO) inhibitors or are within one year of their withdrawal.
16. Acute liver injury (such as hepatitis) or severe cirrhosis (Child-Pugh Class C).
17. Patients with suspected Restless leg syndrome (RLS).
18. Abnormal thyroid-stimulating hormone (TSH) concentrations (according to the references value of the local laboratory).
19. Vitamin B12 and folic acid deficiency (according to the reference values of the local laboratory).
20. Surgical procedures planned to occur during trial (patients may be rescreened following completion of and recovery from the surgical procedure).
21. Concomitant treatment that might influence the final therapeutic effect of the tested active substances including non-medical treatments.
22. Patients who under the opinion of the investigator will not be compliant to the treatment or not be able to finish the trial for any other reason.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. The proportion of patients with clinically meaningful improvement of pain in PDPN after a 12 week treatment with pregabalin.
2. The proportion of patients with clinically meaningful improvement of pain in PDPN after a 12 week treatment with duloxetine.
Improvement of pain in PDPN is considered as clinically meaningful if reduction of average pain intensity in PDPN in last 24-h (measured by VAS) is equal or more than 30 % in comparison to the initial level (baseline) AND/OR if averege pain intensity in PDPN in last 24-h (measured by VAS) does not exceed 30 mm at the end of the trial (after 12 weeks).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 12 weeks of treatment |
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| E.5.2 | Secondary end point(s) |
1. The proportion of patients with reduction of pain in PDPN (measured by VAS) for equal or more than 30 % in comparison to the initial level (baseline) AND/OR with pain intensity in PDPN not exceeding 30 mm (measured by VAS) taking into consideration:
i. current pain intensity (measured at doctor’s office)
ii. average pain intensity in last 24-h
iii. worst pain intensity in last 24-h
[Time Frame: week 1, week 2, week 6, week 8].
2. The proportion of patients with reduction of pain in PDPN for equal or more than 30 % (measured by VAS) in comparison to the initial level (baseline) AND/OR with pain intensity in PDPN not exceeding 30 mm (measured by VAS) taking into consideration:
i. average pain intensity in last 4 weeks
ii. worst pain intensity in last 4 weeks
[Time Frame: week 8, week 12].
3. Pain intensity difference in PDPN (measured by VAS) between each control visit/ phone call and the baseline value at Visit 2:
i. current pain intensity
ii. average pain intensity in last 24-h
iii. worst pain intensity in last 24-h
[Time Frame: week 1, week 2, week 6, week 8, week 12].
4. Pain intensity difference in PDPN (measured by VAS) between Visits 4 and 5 and the baseline value at Visit 2:
i. average pain intensity in last 4 weeks
ii. worst pain intensity in last 4 weeks
[Time Frame: week 8, week 12].
5. The proportion of patients with reduction of pain in PDPN (measured by VAS) for equal or more than 50 % taking into consideration:
i. current pain intensity (measured at doctor’s office)
ii. average pain intensity in last 24-h
iii. worst pain intensity in last 24-h
[Time Frame: Baseline vs.: week 1, week 2, week 6, week 8, week 12].
6. The proportion of patients with reduction of pain in PDPN (measured by VAS) for equal or more than 50 % taking into consideration:
i. average pain intensity in last 4 weeks
ii. worst pain intensity in last 4 weeks
[Time Frame: week 8, week 12].
7. The proportion of patients with eliminated pain in PDPN, which includes intensity of pain in PDPN not exceeding 10 mm (measured by VAS) taking into consideration:
i. current pain intensity (measured at doctor’s office)
ii. average pain intensity in last 24-h
iii. worst pain intensity in last 24-h
[Time Frame: week 6, week 8, week 12].
8. The proportion of patients with eliminated pain in PDPN, which includes intensity of pain in PDPN not exceeding 10 mm (measured by VAS) taking into consideration:
i. average pain intensity in last 4 weeks
ii. worst pain intensity in last 4 weeks
[Time Frame: week 8, week 12].
9. Dose-related efficacy
[Time Frame: week 12].
10. DN4 score difference
11. Quality of life (QoL) difference with 36-Item Short Form Survey Instrument (SF-36)
12. The Montreal Cognitive Assessment (MoCA) score difference for cognitive improvement
13. Insomnia severity index (ISI) difference for sleep
14. Epworth Sleepiness Scale (ESS) score for daytime sleepiness improvement
15. Major depression inventory (MDI) score difference for improvement of major depression
16. Proportion of compliant patients, i.e. those having a compliance of more than 80 % at the regular therapy end visit
[Time Frame: week 2, week 8, week 12] |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Point 1: after 1, 2, 6 and 8 weeks of treatment
Point 2: after 8 and 12 weeks of treatment
Point 3: after 1, 2, 6, 8 and 12 weeks of treatment
Point 4: after 8 and 12 weeks of treatment
Point 5: baseline vs: 1, 2, 6, 8 and 12 weeks of treatment
Point 6: after 8 and 12 weeks of treatment
Point 7: after 6, 8 and 12 weeks of treatment
Point 8: after 8 and 12 weeks of treatment
Point 9: after 12 weeks of treatment
Point 16: after 2, 8 and 12 weeks of treatment |
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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 | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| North Macedonia |
| Serbia |
| Croatia |
| Poland |
| Slovenia |
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| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| 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 | 4 |
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