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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04246619
Recruitment Status : Recruiting
First Posted : January 29, 2020
Last Update Posted : January 29, 2020
Sponsor:
Collaborators:
3ARH
INTERBORA
University Medical Centre Maribor
Information provided by (Responsible Party):
KRKA

Brief Summary:

The objective and the purpose of the trial is to: assess the efficacy of Pregabalin Krka and Dulsevia® 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.

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

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.

On Visit 2 investigator checks the results of laboratory tests, of pregnancy test, measures vital signs, evaluates pain in PDPN according to VAS, 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) - tretament with Pregabalin Krka OR treatment with Dulsevia®.

Investigator performs assessments of: QoL, sleep quality and daytime sleepiness, depression and adverse events.

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.

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, IMP are adjusted and assessment of adverse events is carried out.

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.


Condition or disease Intervention/treatment Phase
Painful Diabetic Peripheral Neuropathy Drug: Pregabalin Drug: Duloxetine Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 310 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Treatment is started at Visit 2 with Pregabalin Krka or Dulsevia - according to randomisation.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy of Pregabalin and Duloxetine in Patients With Painful Diabetic Peripheral Neuropathy (PDPN): the Effect of Pain on Cognitive Function, Sleep and Quality of Life (BLOSSOM)
Actual Study Start Date : November 12, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pregabalin Krka Arm

ARM 1: pregabalin (Pregabalin Krka 25-150 mg/ day) FLEXIBLE-DOSE REGIMEN.

Investigator can choose on V2:

  • Total Pregabalin Krka daily dose: 25 mg/day
  • Total Pregabalin Krka daily dose: 50 mg/day
  • Total Pregabalin Krka daily dose: 75 mg/day
  • Total Pregabalin Krka daily dose: 150 mg/day
  • Total Pregabalin Krka daily dose: 300 mg/day (from Phone call 1 further on)

V3: daily dose should be achieved: MINIMUM dose 150 mg/day Investigator can choose: total Pregabalin Krka daily dose 150 mg/day or 300 mg/day or 600 mg/day Investigator can choose: total Pregabalin Krka daily dose 150 mg/day or 300 mg/day or 600 mg/day

V4: Investigator can choose: total Pregabalin Krka daily dose 150 mg/day or 300 mg/day or 600 mg/day

Drug: Pregabalin

Pregabalin Krka (pregabalin) hard capsules of different strenghts: 25 mg, 75 mg, 150 mg, 300 mg.

Duration: 12 weeks


Experimental: Dulsevia® Arm

• ARM 2: duloxetine (Dulsevia® 30-60 mg/ day) FLEXIBLE-DOSE REGIMEN:

Investigator can choose on V2:

  • Total Dulsevia® daily dose: 30 mg/day
  • Total Dulsevia® daily dose: 60 mg/day

V3: daily dose should be achieved: MINIMUM dose 60 mg/day Investigator can choose total Dulsevia® daily dose 60 mg/day or 90 mg/day or 120 mg/day.

V4: Investigator can choose total Dulsevia® daily dose 60 mg/day or 90 mg/day or 120 mg/day.

Drug: Duloxetine

Dulsevia® (duloxetine) hard gastro-resistant capsules of different strenghts: 30 mg and 60 mg.

Duration: 12 weeks





Primary Outcome Measures :
  1. Clinically meaningful improvement of pain in PDPN after a 12 week treatment with pregabalin [ Time Frame: 12 weeks ]
    Clinically meaningful improvement of pain in PDPN after a 12 week treatment according to VAS

  2. Clinically meaningful improvement of pain in PDPN after a 12 week treatment with duloxetine [ Time Frame: 12 weeks ]
    Clinically meaningful improvement of pain in PDPN after a 12 week treatment according to VAS


Secondary Outcome Measures :
  1. The proportion of patients with reduction of pain in PDPN for equal or more than 30 % AND/OR with pain intensity in PDPN not exceeding 30 mm [ Time Frame: week 1, week 2, week 6, week 8 ]

    The proportion of patients with reduction of pain in PDPN (measured by VAS) for equal or more than 30 % 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


  2. The proportion of patients with reduction of pain in PDPN for equal or more than 30 % AND/OR with pain intensity in PDPN not exceeding 30 mm [ Time Frame: week 8, week 12 ]

    The proportion of patients with reduction of pain in PDPN for equal or more than 30 % (measured by VAS) 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


  3. Pain intensity difference in PDPN [ Time Frame: week 1, week 2, week 6, week 8, week 12 ]

    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 (measured at doctor's office)

    ii. average pain intensity in last 24-h

    iii. worst pain intensity in last 24-h


  4. Pain intensity difference in PDPN [ Time Frame: week 8, week 12 ]

    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 week


  5. The proportion of patients with reduction of pain in PDPN for equal or more than 50 % [ Time Frame: Baseline vs.: week 1, week 2, week 6, week 8, week 12 ]

    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


  6. The proportion of patients with reduction of pain in PDPN for equal or more than 50 % [ Time Frame: week 8, week 12 ]

    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


  7. The proportion of patients with eliminated pain in PDPN [ Time Frame: week 6, week 8, week 12 ]

    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


  8. The proportion of patients with eliminated pain in PDPN [ Time Frame: week 8, week 12 ]

    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


  9. Dose-related efficacy [ Time Frame: week 2, week 8, week 12 ]
    Changes of efficacy according to changing of doses

  10. DN4 score difference [ Time Frame: baseline, week 12 ]
    Mean changes of scores

  11. Quality of life (QoL) difference with 36-Item Short Form Survey Instrument (SF-36) [ Time Frame: baseline, week 12 ]
    Mean changes of scores

  12. The Montreal Cognitive Assessment (MoCA) score difference for cognitive improvement [ Time Frame: week 1, week 12 ]
    Mean changes of scores

  13. Insomnia severity index (ISI) difference for sleep [ Time Frame: baseline, week 12 ]
    Mean changes of scores

  14. Epworth Sleepiness Scale (ESS) score for daytime sleepiness improvement [ Time Frame: baseline, week 12 ]
    Mean changes of scores

  15. Major depression inventory (MDI) score difference for improvement of major depression [ Time Frame: baseline, week 12 ]
    Mean changes of scores

  16. Proportion of compliant patients [ Time Frame: week 2, week 8, week 12 ]
    Proportion of compliant patients, i.e. those having a compliance of more than 80 % at the regular therapy end visit



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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.

The methods for inclusion criteria assessment include medical history, interview, completing the DN4 questionnaire, physical examination, assesment of pain on VAS and laboratory analyses.

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, 4.2. 60 mg of duloxetine, 4.3. 150 mg of venlafaxine, 4.4. 600 mg of gabapentin.

  5. Patients with an uncontrolled type 2 diabetes mellitus.
  6. The average scores of less than 20 on 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 a 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.

    • Highly effective contraception is:

      • combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation(oral, intravaginal, transdermal)
      • progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
      • intrauterine device (IUD)
      • intrauterine hormone-releasing system (IUS)
      • bilateral tubal occlusion
      • vasectomised partner
      • sexual abstinence

        **Acceptable contraception is:

      • progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
      • male or female condom with or without spermicide
      • cap, diaphragm or sponge with spermicide

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04246619


Contacts
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Contact: Vesna Bohinc Sever +386 1 475 1256 vesna.bohinc-sever@krka.biz
Contact: Tanja Kohek +386 1 475 1236 tanja.kohek@krka.biz

Locations
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Croatia
Opća bolnica Karlovac Recruiting
Karlovac, Croatia
Clinical Medical Center Osijek Recruiting
Osijek, Croatia
KB Merkur, Sveučilišna klinika Vuk Vrhovac Recruiting
Zagreb, Croatia
Klinička bolnica Sveti Duh Not yet recruiting
Zagreb, Croatia
North Macedonia
JZU Univerzitetska klinika za endokrinologija, dijabetes I metabolicki bolesti - Skopje Not yet recruiting
Skopje, North Macedonia
JZU Univerzitetska klinika za nevrologija Not yet recruiting
Skopje, North Macedonia
Poland
Gabinet Neurologiczny, prof. Adam Stępień Not yet recruiting
Warszawa, Poland
Poradnia neurologiczna, Centrum terapii dzieci i Dorosłych FIMEDICA Sp. z o.o. Not yet recruiting
Warszawa, Poland
Serbia
Klinički centar Srbije Not yet recruiting
Belgrade, Serbia
Klinički centar Niš Not yet recruiting
Niš, Serbia
Klinički centar Vojvodine Not yet recruiting
Novi Sad, Serbia
Slovenia
Zdravstveni dom Koper Recruiting
Koper, Slovenia, 6000
Clemenz Marjetka - Nevrološka Ordinacija Recruiting
Ljubljana, Slovenia, 1000
Sponsors and Collaborators
KRKA
3ARH
INTERBORA
University Medical Centre Maribor
Investigators
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Study Chair: Martin Rakuša University Medical Centre Maribor
Additional Information:
Publications:

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Responsible Party: KRKA
ClinicalTrials.gov Identifier: NCT04246619    
Other Study ID Numbers: KCT 11/2017
2017-004341-24 ( EudraCT Number )
First Posted: January 29, 2020    Key Record Dates
Last Update Posted: January 29, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Peripheral Nervous System Diseases
Diabetic Neuropathies
Pain
Neuromuscular Diseases
Nervous System Diseases
Neurologic Manifestations
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Pregabalin
Duloxetine Hydrochloride
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anticonvulsants
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Serotonin and Noradrenaline Reuptake Inhibitors
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Antidepressive Agents
Dopamine Agents