Efficacy of Pregabalin and Duloxetine in Patients With PDPN: the Effect of Pain on Cognitive Function, Sleep and Quality of Life

During the 3 months (12 weeks) 5 visits and 2 phone calls are planned.

Procedures and administration:

On arrival at the trial site at Visit 1 the patient receives the complete information on the trial procedures. The patient confirms his decision to participate by signing the informed consent form (ICF). After the ICF signature and before therapy is allocated, a screening procedure is carried out to verify eligibility: laboratory analyses (concentrations of TSH, vitamin B12, folic acid, glucose, HbA1c, pregnancy test for women of childbearing potential), assessment of PDPN (with questionnaire DN4), assessment of cognition (with questionnaire MoCA), habits, medical history (medical/surgical history and concomitant diseases, previous and/or existing therapy of pain in PDPN, concomitant medications) with measurements and evaluation of pain according to VAS.

Patient is instructed not to take any PDPN medication and/or analgesics, if existing on a day of Visit 2.

Information obtained at Visit 1 is input in the eCRF.

Visit 2 (initial baseline visit): 0-7 days after Visit 1

Investigator checks the results of laboratory tests, of pregnancy test, measures vital signs (heart rate, blood pressure), evaluates pain in PDPN according to VAS (separate assessments of current pain intensity, average pain intensity in last 24-h, worst pain intensity in last 24-h, average pain intensity in last 4 weeks and worst pain intensity in last 4 weeks), checks previous analgesic therapy and concomitant medications.

If patient meets all inclusion and exclusion criteria, he/she is eligible and will be randomly assigned (automatically through electronic version of case report form (eCRF) into two therapy groups (treatment arms).

Investigator performs assessments of: QoL (with questionnaire SF-36), sleep quality and daytime sleepiness (with questionnaires ISI and ESS), depression (with questionnaire MDI) and adverse events.

Administration:

Eligible screened patients are randomly assigned into two therapy groups (treatment arms):

ARM 1: treatment with pregabalin (Pregabalin Krka) or ARM 2: treatment with duloxetine (Dulsevia®).

Each patient receives a Patient diary number 1, including the doses of Pregabalin Krka or Dulsevia® (depending on randomization) from Visit 2 (day 1) till Phone call 1, scales for assessing the pain and with the date of Phone call 1.

Treatment during PERIOD 1 (FLEXIBLE-DOSE REGIMEN during the first 14 days (±3 days) in order to allow the investigator to give each patient an optimal dose of IMP.

• ARM 1: pregabalin (Pregabalin Krka 25-150 mg/ day) FLEXIBLE-DOSE REGIMEN. Investigator can choose total Pregabalin Krka daily dose: 25 mg/day, 50 mg/day, 75 mg/day, 150 mg/day or 300 mg/day (from Phone call 1 further on)
• ARM 2: duloxetine (Dulsevia® 30-60 mg/ day) FLEXIBLE-DOSE REGIMEN:

Investigator can choose total Dulsevia® daily dose: 30 mg/day or 60 mg/day

At the Visit 2, RM is given to each patient to cover the treatment till the next Visit 3.

Phone call 1: week 1 (± 3 days) At week 1 (7 ± 3 days after Visit 2) investigator calls the patient by phone and ask him or her about possible adverse events and to evaluate the pain intensity in PDPN by VAS which is a part of Patient diary 1.

Investigator can adjust the dose of IMP during phone call:

• If average pain intensity in PDPN in last 24-h equal or below 30 mm (measured by VAS) is NOT achieved, the investigator can increase the dose;
• if bothersome adverse event occurs the investigator can decrease the dose (if possible).

The investigator also ask the patient if he or she is taking the IMP appropriately (according to investigator's instructions).

NOTE: On the next visit (Visit 3; 14 ± 3 days after Visit 2) following daily doses should be achieved by each patient:

• ARM 1: Total Pregabalin Krka daily dose: MINIMUM dose 150 mg/day
• ARM 2: Total Dulsevia daily dose: MINIMUM dose 60 mg/day

Visit 3: week 2 (14 ± 3 days after Visit 2) At Visit 3, compliance monitoring is done, pain intensity in PDPN by VAS is evaluated, concomitant therapy is checked, vital signs are measured, doses of IMP are adjusted and adverse events assessment are carried out.

Investigator collects the Patient Diary 1. Data in Patient Diary 1 are checked.Treatment during PERIOD 2 (it lasts 6 weeks)

Treatment options:

ARM 1: pregabalin (Pregabalin Krka) Investigator can choose: total Pregabalin Krka daily dose: 150 mg/day or 300 mg/day or 600 mg/day

NOTE:

If in the opinion of the investigator the minimum IMP dose of 150 mg of Pregabalin Krka/ 60 mg of Dulsevia® can not be reached after Visit 3, the patient must be excluded from the trial.

ARM 2: duloxetine (Dulsevia®)

Investigator can choose:

• total Dulsevia® daily dose*: 60 mg/day or 90 mg/day* or total Dulsevia® daily dose**: 120 mg/day
• once daily dosing by using available dosages. **the daily dose will be achieved with two devided doses of Dulsevia® by using available dosages.

ARM 1: pregabalin (Pregabalin Krka)

• If average pain intensity in PDPN in last 24-h equal or below 30 mm (measured by VAS) or reduction of pain equal or more than 30 % compared with baseline is achieved during period 1, further treatment with Pregabalin Krka 150 mg/day or 300 mg/day in the period 2 is required.
• If average pain intensity in PDPN in last 24-h equal or below 30 mm (measured by VAS) or reduction of pain equal or more than 30 % compared with baseline is NOT achieved, further treatment with a dose of:
• 150 mg/day (if patient was till now treated with equal dose) or 300 mg/day (if patient was till now treated with equal dose to 150 mg or 300 mg) or 600 mg/day (if patient was till now treated with equal dose to 300 mg) is required.

ARM 2: duloxetine (Dulsevia®)

• If average pain intensity in PDPN in last 24-h equal or below 30 mm (measured by VAS) or reduction of pain equal or more than 30 % compared with baseline is achieved further treatment with Dulsevia® 60 mg/day in the period 2 is required.
• If average pain intensity in PDPN in last 24-h equal or below 30 mm (measured by VAS) or reduction of pain equal or more than 30 % compared with baseline is NOT achieved, further treatment with the dose of:
• Dulsevia® 60 mg/day (if patient was till now treated with equal dose) or Dulsevia® 90 mg/day (if patient was till now treated with lower dose) or Dulsevia® 120 mg/day (if patient was till now treted with lower dose) is required.

At the Visit 3, RM is given to each patient to cover the treatment till the next Visit 4. Patient is requested to bring packages with all blisters (empty blisters and blister with unused IMPs and RM) on the Visit 4.

Each patient receives a Patient diary number 2, including the doses of Pregabalin Krka or Dulsevia® (depending on randomization) from Visit 3 till Phone call 2, scales for assessing the pain and with the date of Phone call 2 (28 ± 3 days after Visit 3).

Patient is requested to bring the Patient diary on the next visit.

Information obtained at Visit 3 is input in the eCRF.

Phone call 2: 4 weeks(28 ± 3 days) after visit 3 At week 6 (28 ± 3 days after Visit 3) the investigator again calls the patient by phone and asks him or her about possible bothersome adverse events and to evaluate the pain intensity in PDPN by VAS (separate assessments of current pain intensity, average pain intensity in last 24-h and worst pain intensity in last 24-h) which is a part of Patient diary 2.

The investigator can adjust the dose of Pregabalin Krka or Dulsevia®, if necessary. If average pain intensity in PDPN in last 24-h equal or below 30 mm (measured by VAS) is NOT achieved the investigator can increase the dose and if bothersome adverse event occurs the investigator can decrease the dose to the previous dose.

The investigator also checks if the patient takes the medicines appropriately (according to investigator's instructions).

Visit 4: week 8 (42 ± 3 days after Visit 3) At Visit 4, pregnancy test for women of childbearing potential and compliance monitoring are carried out; concomitant medications are checked, vital signs are measured, pain intensity in PDPN by VAS is evaluated (separate assessments of current pain intensity, average pain intensity in last 24-h and worst pain intensity in last 24-h, average pain intensity in last 4 weeks and worst pain intensity in last 4 weeks), IMP are adjusted and assessment of adverse events is carried out. Investigator collects the Patient Diary 2. Data in Patient Diary 2 are checked.

Treatment options during PERIOD 3 (it lasts 4 weeks) ARM 1: pregabalin (Pregabalin Krka)

Investigator can choose:

Total Pregabalin Krka daily dose: 75 mg/day *,150 mg/day, 300 mg/day or 600 mg/day

*only in case of bothersome adverse events

ARM 2: duloxetine (Dulsevia®) Investigator can choose:Total Dulsevia® daily dose: 30 mg/day*, 60 mg/day, 90 mg/day or 120 mg/day *only in case of bothersome adverse events

Arm 1: pregabalin (Pregabalin Krka)

• If average pain intensity in PDPN in last 24-h equal or below 30 mm (measured by VAS) or reduction of pain equal or more than 30 % compared with Visit 3 is achieved, further treatment with previous dose in the period 3 is required.
• If average pain intensity in PDPN in last 24-h equal or below 30 mm (measured by VAS) or reduction of pain equal or more than 30 % compared with Visit 3 is NOT achieved on daily dose 150 mg, further treatment with a dose of: 150 mg/day (if patient was till now treated with equal dose) or 300 mg/day (if patient was till now treated with lower or equal dose) or 600 mg/day (if patient was till now treted with lower or equal dose) is required.

Arm 2: duloxetine (Dulsevia®)

• If average pain intensity in PDPN in last 24-h equal or below 30 mm (measured by VAS) or reduction of pain equal or more than 30 % compared with Visit 3 is achieved further treatment with previous dose in the period 3 is required.
• If average pain intensity in PDPN in last 24-h equal or below 30 mm (measured by VAS) or reduction of pain equal or more than 30 % compared with Visit 3 is NOT achieved, further treatment with a dose of:

Dulsevia® 60 mg/day (if patient was till now treated with equal dose) or Dulsevia® 90 mg/day (if patient was till now treated with lower or equal dose) or Dulsevia® 120 mg/day (if patient was till now treated with lower or equal dose).

At the Visit 4, RM is given to each patient to cover the treatment till the next Visit 5.

Visit 5: week 12 (28 ± 3 days after Visit 4) At Visit 5 investigator performs again assessments of: QoL, sleep quality and daytime sleepiness, depression, cognition and PDPN.

Evaluation of the pain intensity in PDPN by VAS and assessment of the adverse events should be performed.

Pregnancy test for women of childbearing potential is carried out.

Compliance monitoring, measurement of vital signs and concomitant medications are also carryed out by investigator.