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)
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 发起方
- KRKA
- 入组人数
- 254
- 试验地点
- 13
- 主要终点
- Clinically meaningful improvement of pain in PDPN after a 12 week treatment with pregabalin
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Female and male patients aged 18-85 years.
- •Patients with a history of type 2 diabetes mellitus according to The American Diabetes Association (ADA).
- •Patients with a diagnosis of painful diabetic peripheral neuropathy (PDPN) caused by type 2 diabetes mellitus based on DN4 ≥
- •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').
- •Ability to adhere to trial protocol.
- •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.
排除标准
- •Patients who took PDPN medication and/or analgesics on a day of baseline visit.
- •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.
- •Patients with a history of inadequate pain response (pain reduced was equal or less than 30%) to:
- •pregabalin at maximum allowed treatment daily dose 600 mg, 3.
- •duloxetine at maximum allowed treatment daily dose 120 mg, 3.
- •venlafaxine at maximum allowed treatment daily dose 375 mg, 3.
- •gabapentin on daily treatment dose more than 1800 mg 3.
- •amitriptilin at maximum allowed treatment daily dose 150 mg.
- •Patients, who are currently treated with a daily dose that exceeds:
- •150 mg of pregabalin, 4.
- •60 mg of duloxetine, 4.
- •150 mg of venlafaxine, 4.
- •600 mg of gabapentin.
- •Patients with an uncontrolled type 2 diabetes mellitus.
- •The average scores of less than 20 on MoCA.
- •Have any other type of neuropatic pain, contrasted to PDPN.
- •Evidence of another cause of distal polyneuropathy other than diabetic.
- •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.
- •Have a diagnosis or history of uncontrolled glaucoma.
- •Known or suspected alcohol or drug abuse or addiction (excluding nicotine and caffeine).
- •Patients with a history of depression (less than one year after completing the last medical treatment), mania, bipolar disorder, psychosis or schizophrenia.
- •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).
- •Patients with a history of epilepsy, stroke or neurodegenerative disease.
- •Patients taking Monoamine oxidase (MAO) inhibitors or are within one year of their withdrawal.
- •Acute liver injury (such as hepatitis) or severe cirrhosis (Child-Pugh Class C).
- •Patients with suspected Restless leg syndrome (RLS).
- •Abnormal thyroid-stimulating hormone (TSH) concentrations (according to the references value of the local laboratory).
- •Vitamin B12 and folic acid deficiency (according to the reference values of the local laboratory).
- •Surgical procedures planned to occur during trial (patients may be rescreened following completion of and recovery from the surgical procedure).
- •Concomitant treatment that might influence the final therapeutic effect of the tested active substances including non-medical treatments.
- •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
研究组 & 干预措施
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
干预措施: Pregabalin (Drug)
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.
干预措施: Duloxetine (Drug)
结局指标
主要结局
Clinically meaningful improvement of pain in PDPN after a 12 week treatment with pregabalin
时间窗: 12 weeks
Clinically meaningful improvement of pain in PDPN after a 12 week treatment according to VAS
Clinically meaningful improvement of pain in PDPN after a 12 week treatment with duloxetine
时间窗: 12 weeks
Clinically meaningful improvement of pain in PDPN after a 12 week treatment according to VAS
次要结局
- Epworth Sleepiness Scale (ESS) score for daytime sleepiness improvement(baseline, week 12)
- Major depression inventory (MDI) score difference for improvement of major depression(baseline, week 12)
- The Montreal Cognitive Assessment (MoCA) score difference for cognitive improvement(week 1, week 12)
- 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(week 8, week 12)
- Quality of life (QoL) difference with 36-Item Short Form Survey Instrument (SF-36)(baseline, week 12)
- Insomnia severity index (ISI) difference for sleep(baseline, week 12)
- Pain intensity difference in PDPN(week 8, week 12)
- The proportion of patients with reduction of pain in PDPN for equal or more than 50 %(week 8, week 12)
- The proportion of patients with eliminated pain in PDPN(week 8, week 12)
- DN4 score difference(baseline, week 12)
- Proportion of compliant patients(week 2, week 8, week 12)
- Dose-related efficacy(week 2, week 8, week 12)