Clinical Trial Results:
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)
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Summary
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EudraCT number |
2017-004341-24 |
Trial protocol |
SI PL HR |
Global end of trial date |
21 Dec 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Apr 2023
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First version publication date |
23 Apr 2023
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Other versions |
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Summary report(s) |
BLOSSOM CSR SYNOPSIS |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
KCT11/2017–BLOSSOM
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Krka, d.d., Novo mesto
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Sponsor organisation address |
Dunajska cesta 65, Ljubljana, Slovenia, 1000
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Public contact |
Tanja Kohek, Krka, d.d., Novo mesto
Dunajska cesta 65
1000 Ljubljana, +386 14751236, tanja.kohek@krka.biz
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Scientific contact |
Tanja Kohek, Krka, d.d., Novo mesto
Dunajska cesta 65
1000 Ljubljana, +386 14751236, tanja.kohek@krka.biz
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
11 Nov 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Dec 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Dec 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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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 as well as to assess the safety of Pregabalin Krka and Dulsevia® in patients with PDPN.
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Protection of trial subjects |
Inclusion criteria served to select the homogeneous population with a diagnosis of PDPN caused by type 2 diabetes mellitus. Exclusion criteria also facilitated a reduction of possible biases through selection of study population without concomitant therapy that could influence pain results, excluded patients with a history of inadequate pain response, considered factors, which could influence patient safety. Inclusion and exclusion criteria were, however, permissive enough to allow a selection of the patients.
The use of concomitant medication with known interactions and/or contraindications as related to the study medications was restricted in the interest of patient safety.
During 12 weeks of treatment patients had 5 study visits and two phone calls. The study was divided in screening period with screening visit and initial baseline visit, three treatment periods and the last visit for conclusion of study. Patients were randomly assigned into two treatment arms, Pregabalin Arm and Duloxetine Arm. Patients started taking the allocated study medication on day of baseline visit (Visit 2), after all procedures of the baseline visit were finished.
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Background therapy |
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Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Nov 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
North Macedonia: 58
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Country: Number of subjects enrolled |
Serbia: 18
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Country: Number of subjects enrolled |
Poland: 44
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Country: Number of subjects enrolled |
Slovenia: 14
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Country: Number of subjects enrolled |
Croatia: 67
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Worldwide total number of subjects |
201
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EEA total number of subjects |
125
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
89
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From 65 to 84 years |
112
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85 years and over |
0
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Recruitment
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Recruitment details |
Patient recruitment in the study began in November 2019 (FPI date: 12th November 2019) and was concluded in September 2021 (LPI date: 16th September 2021). A total of 254 patients were screened and 201 patient were allocated to treatment in five participating countries - Croatia, North Macedonia, Poland, Serbia and Slovenia. | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Eligible patients were adults aged 18 to 85 years, with a history of type 2 diabetes mellitus, with a diagnosis of PDPN caused by type 2 diabetes mellitus based on DN4 questionnaire ≥4 and whose pain intensity level in the last 24 hours was more than 40 mm on VAS scale. | |||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Pregabalin Arm | |||||||||||||||||||||||||||||||||
Arm description |
Patients were randomly assigned into two treatment arms, Pregabalin Arm and Duloxetine Arm. The randomisation list was prepared for each study site separately. There were two treatment groups group A for pregabalin and group B for duloxetine. Block size was 4, so the list length was divisible with 4. Pregabalin treatment was preferably started at a daily dose of 150 mg pregabalin. Based on investigator’s opinion, the treatment could have been started at a lower dose 25 mg, 50 mg or 75 mg. Based on individual patient response, tolerability and investigator’s opinion, the dose may have been increased up to 300 mg per day after Phone call 1 (1 week after baseline visit - Visit 2). The minimum dose of 150 mg per day must have been achieved at Visit 3 (2 weeks after Visit 2). After Visit 3 the daily dose of pregabalin could have been increased up to 600mg per day. If necessary, therapy with rescue medicine (Doreta®) could have been initiated from Visit 2. | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Pregabalin Krka 25 mg
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Investigational medicinal product code |
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Other name |
Pragiola®
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Pregabalin Krka 25 mg hard capsules, each capsule contains 25 mg of pregabalin. One capsule was administered once or twice daily, at about the same time each day (± 3 hours) orally, with or without food.
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Investigational medicinal product name |
Pregabalin Krka 75 mg
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Investigational medicinal product code |
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Other name |
Pragiola®
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Pregabalin Krka 75 mg hard capsules, each capsule contains 75 mg of pregabalin. One capsule was administered once or twice daily, at about the same time each day (± 3 hours) orally, with or without food.
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Investigational medicinal product name |
Pregabalin Krka 150 mg
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Investigational medicinal product code |
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Other name |
Pragiola®
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Pregabalin Krka 150 mg hard capsules, each capsule contains 150 mg of pregabalin. One capsule was administered once or twice daily, at about the same time each day (± 3 hours) orally, with or without food.
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Investigational medicinal product name |
Pregabalin Krka 300 mg
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Investigational medicinal product code |
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Other name |
Pragiola®
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Pregabalin Krka 300 mg hard capsules, each capsule contains 300 mg of pregabalin. One capsule was administered once or twice daily, at about the same time each day (± 3 hours) orally, with or without food.
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Investigational medicinal product name |
Doreta® 37.5/325 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Rescue medicine. Doreta® film-coated tablets 37.5 mg/325 mg, each tablet contains 37.5 mg of tramadol hydrochloride equivalent to 32.94 mg tramadol and 325 mg paracetamol. RM must have been taken according to the protocol and investigator`s instructions. Maximum daily dose was 8 tablets (equivalent to 300 mg tramadol hydrochloride and 2600 mg paracetamol). The dosing interval for RM should not have been less than six hours with maximum two tablets taken per once.
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Arm title
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Duloxetine Arm | |||||||||||||||||||||||||||||||||
Arm description |
Patients were randomly assigned into two treatment arms, Pregabalin Arm and Duloxetine Arm. The randomisation list was prepared for each study site separately. There were two treatment groups group A for pregabalin and group B for duloxetine. Block size was 4, so the list length was divisible with 4. Duloxetine treatment could be started at a dose of 30 mg or 60 mg of duloxetine per day. Based on individual patient response, tolerability and investigator’s opinion the dose may have been increased up to 60 mg per day after an interval of 1 to 14 days. The minimum dose of 60 mg per day must have been achieved at Visit 3 (2 weeks after baseline visit - Visit 2). After Visit 3 the daily dose of duloxetine could have been increased up to 90 or 120 mg per day. If necessary, therapy with rescue medicine (Doreta®) could have been initiated from Visit 2. | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Dulsevia® 30 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Dulsevia® 30 mg hard gastro-resistant capsules, each capsule contains 30 mg of duloxetine (as hydrochloride). One capsule was administered once or twice daily, at about the same time each day (± 3 hours) orally, with or without food.
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Investigational medicinal product name |
Dulsevia® 60 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Dulsevia® 60 mg hard gastro-resistant capsules, each capsule contains 60 mg of duloxetine (as hydrochloride). One capsule was administered once or twice daily, at about the same time each day (± 3 hours) orally, with or without food.
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Investigational medicinal product name |
Doreta® 37.5/325 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Rescue medicine. Doreta® film-coated tablets 37.5 mg/325 mg, each tablet contains 37.5 mg of tramadol hydrochloride equivalent to 32.94 mg tramadol and 325 mg paracetamol. RM must have been taken according to the protocol and investigator`s instructions. Maximum daily dose was 8 tablets (equivalent to 300 mg tramadol hydrochloride and 2600 mg paracetamol). The dosing interval for RM should not have been less than six hours with maximum two tablets taken per once.
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Baseline characteristics reporting groups
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Reporting group title |
Pregabalin Arm
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Reporting group description |
Patients were randomly assigned into two treatment arms, Pregabalin Arm and Duloxetine Arm. The randomisation list was prepared for each study site separately. There were two treatment groups group A for pregabalin and group B for duloxetine. Block size was 4, so the list length was divisible with 4. Pregabalin treatment was preferably started at a daily dose of 150 mg pregabalin. Based on investigator’s opinion, the treatment could have been started at a lower dose 25 mg, 50 mg or 75 mg. Based on individual patient response, tolerability and investigator’s opinion, the dose may have been increased up to 300 mg per day after Phone call 1 (1 week after baseline visit - Visit 2). The minimum dose of 150 mg per day must have been achieved at Visit 3 (2 weeks after Visit 2). After Visit 3 the daily dose of pregabalin could have been increased up to 600mg per day. If necessary, therapy with rescue medicine (Doreta®) could have been initiated from Visit 2. | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Duloxetine Arm
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Reporting group description |
Patients were randomly assigned into two treatment arms, Pregabalin Arm and Duloxetine Arm. The randomisation list was prepared for each study site separately. There were two treatment groups group A for pregabalin and group B for duloxetine. Block size was 4, so the list length was divisible with 4. Duloxetine treatment could be started at a dose of 30 mg or 60 mg of duloxetine per day. Based on individual patient response, tolerability and investigator’s opinion the dose may have been increased up to 60 mg per day after an interval of 1 to 14 days. The minimum dose of 60 mg per day must have been achieved at Visit 3 (2 weeks after baseline visit - Visit 2). After Visit 3 the daily dose of duloxetine could have been increased up to 90 or 120 mg per day. If necessary, therapy with rescue medicine (Doreta®) could have been initiated from Visit 2. | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Pregabalin Arm
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Reporting group description |
Patients were randomly assigned into two treatment arms, Pregabalin Arm and Duloxetine Arm. The randomisation list was prepared for each study site separately. There were two treatment groups group A for pregabalin and group B for duloxetine. Block size was 4, so the list length was divisible with 4. Pregabalin treatment was preferably started at a daily dose of 150 mg pregabalin. Based on investigator’s opinion, the treatment could have been started at a lower dose 25 mg, 50 mg or 75 mg. Based on individual patient response, tolerability and investigator’s opinion, the dose may have been increased up to 300 mg per day after Phone call 1 (1 week after baseline visit - Visit 2). The minimum dose of 150 mg per day must have been achieved at Visit 3 (2 weeks after Visit 2). After Visit 3 the daily dose of pregabalin could have been increased up to 600mg per day. If necessary, therapy with rescue medicine (Doreta®) could have been initiated from Visit 2. | ||
Reporting group title |
Duloxetine Arm
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Reporting group description |
Patients were randomly assigned into two treatment arms, Pregabalin Arm and Duloxetine Arm. The randomisation list was prepared for each study site separately. There were two treatment groups group A for pregabalin and group B for duloxetine. Block size was 4, so the list length was divisible with 4. Duloxetine treatment could be started at a dose of 30 mg or 60 mg of duloxetine per day. Based on individual patient response, tolerability and investigator’s opinion the dose may have been increased up to 60 mg per day after an interval of 1 to 14 days. The minimum dose of 60 mg per day must have been achieved at Visit 3 (2 weeks after baseline visit - Visit 2). After Visit 3 the daily dose of duloxetine could have been increased up to 90 or 120 mg per day. If necessary, therapy with rescue medicine (Doreta®) could have been initiated from Visit 2. | ||
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End point title |
Clinically meaningful improvement of 24h-API after 12 weeks [1] | |||||||||||||||
End point description |
The proportion of patients with clinically meaningful improvement of pain in PDPN after a 12 week treatment with pregabalin and 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 (API) in PDPN in last 24-h (measured by VAS) is equal or more than 30 % in comparison to the initial (baseline) level AND/OR if averege pain intensity in PDPN in last 24-h (measured by VAS) does not exceed 30 mm after 12 weeks of treatment.
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End point type |
Primary
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End point timeframe |
Each patient was monitored for 12 weeks. Timeframe for AE reporting was the same throughout the whole trial.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: For the assessment of each proportion, the two-sided “equal-tails” Clopper-Pearson exact 95%-confidence interval was employed. For a randomized patient, any record from Visit 2 onwards that was necessary for the evaluation of an efficacy endpoint was treated as a missing value if it was unavailable for any reason. Missing values were imputed by means of multiple imputation (MI), and on estimates obtained by MI statistical inference methods specifically devdevised for MI were employed. |
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| No statistical analyses for this end point | ||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Each patient was monitored for 12 weeks. Timeframe for AE reporting was the same throughout the whole trial.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.0
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Reporting groups
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Reporting group title |
Pregabalin Arm
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Reporting group description |
Patients were randomly assigned into two treatment arms, Pregabalin Arm and Duloxetine Arm. The randomisation list was prepared for each study site separately. There were two treatment groups group A for pregabalin and group B for duloxetine. Block size was 4, so the list length was divisible with 4. Pregabalin treatment was preferably started at a daily dose of 150 mg pregabalin. Based on investigator’s opinion, the treatment could have been started at a lower dose 25 mg, 50 mg or 75 mg. Based on individual patient response, tolerability and investigator’s opinion, the dose may have been increased up to 300 mg per day after Phone call 1 (1 week after baseline visit - Visit 2). The minimum dose of 150 mg per day must have been achieved at Visit 3 (2 weeks after Visit 2). After Visit 3 the daily dose of pregabalin could have been increased up to 600mg per day. If necessary, therapy with rescue medicine (Doreta®) could have been initiated from Visit 2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Duloxetine Arm
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Reporting group description |
Patients were randomly assigned into two treatment arms, Pregabalin Arm and Duloxetine Arm. The randomisation list was prepared for each study site separately. There were two treatment groups group A for pregabalin and group B for duloxetine. Block size was 4, so the list length was divisible with 4. Duloxetine treatment could be started at a dose of 30 mg or 60 mg of duloxetine per day. Based on individual patient response, tolerability and investigator’s opinion the dose may have been increased up to 60 mg per day after an interval of 1 to 14 days. The minimum dose of 60 mg per day must have been achieved at Visit 3 (2 weeks after baseline visit - Visit 2). After Visit 3 the daily dose of duloxetine could have been increased up to 90 or 120 mg per day. If necessary, therapy with rescue medicine (Doreta®) could have been initiated from Visit 2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 3% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
