NOBLE: An Interventional Study to Assess the Efficacy and Safety of Buprenorphine in Korean Patients With Spinal Disorders

• Sponsor: Mundipharma Korea Ltd (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01818700
• Collaborator: (none)
• Enrollment: 245
• Location: 1
• Arm: 1
• Duration (Months): 9
• Patients Per Site Per Month: 27.3

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the pain reduction rate after 8 weeks treatment of NORSPAN® from baseline.

And secondary purpose are: pain reduction rate after 4 weeks treatment from baseline(week 0) the EQ-5D, the pain and sleep questionnaire, physician's overall satisfaction subject's overall satisfaction, and safety

Condition or Disease	Intervention/Treatment	Phase
Spinal Disorder	Drug: Buprenorphine	Phase 4

Detailed Description

Upon providing written informed consent, subject will be screened in the study and assessment will be performed at that time such as safety laboratory assessments, physical examination, vital sign, medical history taking, 24 hours pain intensity score, EQ-5D, pain and sleep questionnaire, physician's overall satisfaction and subject's overall satisfaction.

If patient is eligible in inclusion/exclusion criteria at the time of visit 1, the patient will receive treatment with NORSPAN®.

Treatment with NORSPAN® will be started from 5 μg/h (1 patch a week) for 2 weeks, and proper titration (up-titration) will be allowed at visit 2(wk 2) and at visit 3(wk 4) according to the investigator's decision.

Study Design

• Study Type: Interventional
• Actual Enrollment: 245 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: A Multicenter, Phase IV, Interventional Study to Assess the Efficacy and Safety of NORSPAN® (Buprenorphine) in Korean Patients With Spinal Disorders (NOBLE)
• Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Other: Single arm-Norspan patch (Buprenorphine) This trial is single arm with Norspan patch. Treatment with NORSPAN Ò will be started from 5 μg/h (1 patch a week) for 2 weeks, and proper titration (up-titration) will be allowed at visit 2(wk 2) and at visit 3(wk 4) according to the investigator's decision. The up-titration will be considered by investigator's judgement as follows; (1) if the rescue medication was used more than 2 times per day, on average or (2) based on the daily average NRS(Numeric Rating Scale), if the NRS was changed to worsen since the previous visit, (3) Investigator's judgement by considering any titration needed situation (e.g. dose, frequency of rescue medication).

Drug: Buprenorphine; 8weeks treatment with Norspan®(Buprenorphine)

Outcome Measures

Primary Outcome Measures

1. Change of Pain Intensity* at Week 8 of Treatment With the Study Drug From Baseline [8 weeks]

   NRS-Pain scale assessed the severity of a subject's lower back pain on a scale of 0 (No pain) and 10 (Worst possible pain). NRS-Pain scale: Change = mean score at Week 8/ET minus mean score at Baseline.

Secondary Outcome Measures

1. Change of Pain Intensity at 4 Week of Treatment With Study Srug From Baseline. [4 weeks]

   NRS-Pain scale assessed the severity of a subject's lower back pain on a scale of 0 (No pain) and 10 (Worst possible pain). NRS-Pain scale: Change = mean score at Week 4/ET minus mean score at Baseline.

2. Change in Quality of Life at 8 Week of Treatment With Study Drug From Baseline [8 weeks]

   The Euroqol Health Survey (EQ-5D, 3-level) was completed on five dimensions (mobility, self care, usual activities, pain/discomfort and anxiety/depression) to measure health-related quality of life on a scale from 0-1. A higher score indicates better quality of life. EQ-5D score = 1 - 0.081 - (relevant score by level for the relevant item)-0.269 (only if there is at least one level 3). Table of scores by level for EQ-5D items mobility(level 1=0, level2=0.069,level 3=0.314), self care(level 1=0, level2=0.104,level 3=0.214), usual activities(level 1=0, level2=0.036,level 3=0.094), pain/discomfort (level 1=0, level2=0.,level 3=0.386) and anxiety/depression(level 1=0, level2=0.071,level 3=0.236).

3. Change of EQ-VAS at 8 Weeks of Treatment With Study Drug From Baseline. [8 week]

   EQ-5D Visual Analogue Scale (VAS) in rates the participant's overall health status using values from 0 (worst imaginable) to 100 (best imaginable).

4. Clinician Global Impression of Change(CGIC) [8weeks]

   Number of clinician with categorical change in overall status. CGIC: a clinician-rated instrument assessing change in clinician's overall status from baseline, on a scale ranging from 1 (very much improved) to 7 (very much worse).

5. Patients Global Impression og Change(PGIC) [8 week]

   Number of clinician with categorical change in overall status. PGIC: a participant-rated instrument assessing change in patient's overall status from baseline, on a scale ranging from 1 (very much improved) to 7 (very much worse).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 20 years old or above male or female Korean patients

• Patients who have spinal disorders related pain

• Patients who had been treated with weak opioids and/or NSAIDs before study participation

• Patients who have moderate to severe pain intensity

• Naïve patients for Buprenorphine (Naïve patient are defined as those who had not been treated with Buprenorphine for 90 days)

• Patients who signed a written informed consent form

Exclusion Criteria:

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant. UNLESS they are:

• women whose partners have been sterilized by vasectomy or other means

• using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method. Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent.

• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive urine pregnancy test

• Patients with known hypersensitivity to buprenorphine or to any of the excipients

• Patients with severely impaired respiratory function or respiratory depression status

• Patients concurrently receiving MAOIs or who have received MAOIs within the previous two weeks

• Patients with convulsive disorders, head injury, shock, a reduced level of consciousness of uncertain origin, intracranial lesions or increased intracranial pressure, or in patients with severe hepatic impairment

• Patients with biliary tract disorders

• Patients known to have, or suspected of having a history of drug abuse

• Patients with history of opioid or drug dependence

• Patients who are concurrently taking other CNS depressants or muscle relaxants that may cause respiratory depression, hypotension, profound sedation or potentially result in coma.

• Patients who are taking Buprenorphine or strong opioid.

• Any situation where Buprenorphine is contraindicated

• Major surgery within 1 month prior to screening or planned surgery Mainly pain originated other than spinal disorders disease

• Non-malignant patients or cancer patients who are receiving any oncology treatment that could affect the measure of pain control

• With a disability that may prevent the patient from completing all study requirements and in particular, interfere with 24hrs pain intensity score

• Clinically significant impairment of cardiovascular, respiratory and renal function

• Patient who needs acute dose titration or whose pain intensity fluctuate significantly in a short period according to investigator's judgment

• Having used other investigational drugs at the time of enrollment, or within 30 days of enrollment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Samsung Medical Center	Seoul		Korea, Republic of

Sponsors and Collaborators

• Mundipharma Korea Ltd

Investigators

• Principal Investigator: Whan Eoh, Samsung Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mundipharma Korea Ltd
• ClinicalTrials.gov Identifier: NCT01818700
• Other Study ID Numbers: BUP12-KR-401
• First Posted: Mar 26, 2013
• Last Update Posted: Oct 22, 2015
• Last Verified: Oct 1, 2015

• Additional relevant MeSH terms: Spinal Diseases; Buprenorphine

Study Results

Participant Flow

Recruitment Details	Duration of study: from 16 Oct. 2012 to 28 Jun 2013
Pre-assignment Detail	This study is single arm for Norspan(buprenorphine) patch. Treatment with NORSPAN will be started from 5 μg/h for 2 weeks, and proper titration(up-titration) will be allowed at visit 2(wk 2) and at visit 3(wk 4) according to the investigator's decision. judgement by considering any titration needed situation.

Arm/Group Title	Single Arm - Norspan Patch (Buprenorphine)
Arm/Group Description	This study is single arm for Norspan(buprenorphine) patch. Treatment with NORSPAN Ò will be started from 5 μg/h (1 patch a week) for 2 weeks, and proper titration (up-titration) will be allowed at visit 2(wk 2) and at visit 3(wk 4) according to the investigator's decision. The up-titration will be considered by investigator's judgement as follows; (1) if the rescue medication was used more than 2 times per day, on average or (2) based on the daily average NRS(Numeric Rating Scale), if the NRS was changed to worsen since the previous visit, (3) Investigator's judgement by considering any titration needed situation (e.g. dose, frequency of rescue medication).
Period Title: Overall Study
STARTED	245
Safety Set	241
FAS Set	210
PP Set	105
COMPLETED	141
NOT COMPLETED	104

Baseline Characteristics

Arm/Group Title	Norspan Patch (Buprenorphine)
Arm/Group Description	Trade name is Norspan. Buprenorphine 5μg/h, 10 μg/h, 20 μg/h patches will be used (4 patches a box). Patch will be administered every 7th day. Buprenorphine: 8weeks treatment with Norspan®(Buprenorphine)
Overall Participants	241
Age, Customized (years) [Mean (Standard Deviation) ]
Age	63.51 (11.53)
Sex: Female, Male (Count of Participants)
Female	167 69.3%
Male	74 30.7%
Region of Enrollment (participants) [Number]
Korea, Republic of	241 100%

Outcome Measures

1. Primary Outcome

Title	Change of Pain Intensity* at Week 8 of Treatment With the Study Drug From Baseline
Description	NRS-Pain scale assessed the severity of a subject's lower back pain on a scale of 0 (No pain) and 10 (Worst possible pain). NRS-Pain scale: Change = mean score at Week 8/ET minus mean score at Baseline.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

FAS set: 210. Missing values were imputed by LOCF FAS included the data obtained from all subjects who had at least one dose of the study drug and had data of at least one primary efficacy endpoint assessment.

Arm/Group Title	Single Arm-Norspan Patch (Buprenorphine)
Arm/Group Description	This study is single study with buprenorphine. Treatment with NORSPAN Ò will be started from 5 μg/h (1 patch a week) for 2 weeks, and proper titration (up-titration) will be allowed at visit 2(wk 2) and at visit 3(wk 4) according to the investigator's decision. The up-titration will be considered by investigator's judgement as follows; (1) if the rescue medication was used more than 2 times per day, on average or (2) based on the daily average NRS(Numeric Rating Scale), if the NRS was changed to worsen since the previous visit, (3) Investigator's judgement by considering any titration needed situation (e.g. dose, frequency of rescue medication).
Measure Participants	210
Mean (Standard Deviation) [units on a scale]	-1.65 (1.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single Arm-Norspan Patch (Buprenorphine)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments	The primary endpoint will be the actual reduction rate of pain intensity (0 -10) score at 8 weeks. It will be analyzed by using paired t-test.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.65
	Confidence Interval	(2-Sided) 95%; -10 to 10
	Parameter Dispersion	Type: Standard Deviation; Value: 1.96
	Estimation Comments

2. Secondary Outcome

Title	Change of Pain Intensity at 4 Week of Treatment With Study Srug From Baseline.
Description	NRS-Pain scale assessed the severity of a subject's lower back pain on a scale of 0 (No pain) and 10 (Worst possible pain). NRS-Pain scale: Change = mean score at Week 4/ET minus mean score at Baseline.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

FAS set: 210. Missing values were imputed LOCF.

Arm/Group Title	Single Arm-Norspan Patch (Buprenorphine)
Arm/Group Description	This trial is single arm with Norspan patch. Treatment with NORSPAN Ò will be started from 5 μg/h (1 patch a week) for 2 weeks, and proper titration (up-titration) will be allowed at visit 2(wk 2) and at visit 3(wk 4) according to the investigator's decision. The up-titration will be considered by investigator's judgement as follows; (1) if the rescue medication was used more than 2 times per day, on average or (2) based on the daily average NRS(Numeric Rating Scale), if the NRS was changed to worsen since the previous visit, (3) Investigator's judgement by considering any titration needed situation (e.g. dose, frequency of rescue medication). Buprenorphine: 8weeks treatment with Norspan®(Buprenorphine)
Measure Participants	210
Mean (Standard Deviation) [units on a scale]	-1.26 (1.71)

3. Secondary Outcome

Title	Change in Quality of Life at 8 Week of Treatment With Study Drug From Baseline
Description	The Euroqol Health Survey (EQ-5D, 3-level) was completed on five dimensions (mobility, self care, usual activities, pain/discomfort and anxiety/depression) to measure health-related quality of life on a scale from 0-1. A higher score indicates better quality of life. EQ-5D score = 1 - 0.081 - (relevant score by level for the relevant item)-0.269 (only if there is at least one level 3). Table of scores by level for EQ-5D items mobility(level 1=0, level2=0.069,level 3=0.314), self care(level 1=0, level2=0.104,level 3=0.214), usual activities(level 1=0, level2=0.036,level 3=0.094), pain/discomfort (level 1=0, level2=0.,level 3=0.386) and anxiety/depression(level 1=0, level2=0.071,level 3=0.236).
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

FAS set: 210. Missing values were imputed by LOCF. Even though 210 subjects at Visit 1, baseline were assessed EQ-5D questionnaire, At visit 4(8weeks), 153 subjects were assessed EQ-5D questionnaire.

Arm/Group Title	Single Arm - Norspan Patch (Buprenorphine)
Arm/Group Description	This study is single arm for Norspan(buprenorphine) patch. Treatment with NORSPAN Ò will be started from 5 μg/h (1 patch a week) for 2 weeks, and proper titration (up-titration) will be allowed at visit 2(wk 2) and at visit 3(wk 4) according to the investigator's decision. The up-titration will be considered by investigator's judgement as follows; (1) if the rescue medication was used more than 2 times per day, on average or (2) based on the daily average NRS(Numeric Rating Scale), if the NRS was changed to worsen since the previous visit, (3) Investigator's judgement by considering any titration needed situation (e.g. dose, frequency of rescue medication).
Measure Participants	153
Mean (Standard Deviation) [units on a scale]	0.18 (0.31)

4. Secondary Outcome

Title	Change of EQ-VAS at 8 Weeks of Treatment With Study Drug From Baseline.
Description	EQ-5D Visual Analogue Scale (VAS) in rates the participant's overall health status using values from 0 (worst imaginable) to 100 (best imaginable).
Time Frame	8 week

Outcome Measure Data

Analysis Population Description

FAS set: 210. Missing values were imputed by LOCF. Even though 210 subjects were assessed EQ-VAS at visit 1(baseline), 153 Subjects were assessed EQ-VAS at visit 4(8week)

Arm/Group Title	Single Arm - Norspan Patch (Buprenorphine)
Arm/Group Description	This study is single arm for Norspan(buprenorphine) patch. Treatment with NORSPAN Ò will be started from 5 μg/h (1 patch a week) for 2 weeks, and proper titration (up-titration) will be allowed at visit 2(wk 2) and at visit 3(wk 4) according to the investigator's decision. The up-titration will be considered by investigator's judgement as follows; (1) if the rescue medication was used more than 2 times per day, on average or (2) based on the daily average NRS(Numeric Rating Scale), if the NRS was changed to worsen since the previous visit, (3) Investigator's judgement by considering any titration needed situation (e.g. dose, frequency of rescue medication).
Measure Participants	153
Mean (Standard Deviation) [units on a scale]	10.55 (24.76)

5. Secondary Outcome

Title	Clinician Global Impression of Change(CGIC)
Description	Number of clinician with categorical change in overall status. CGIC: a clinician-rated instrument assessing change in clinician's overall status from baseline, on a scale ranging from 1 (very much improved) to 7 (very much worse).
Time Frame	8weeks

Outcome Measure Data

Analysis Population Description

FAS set: 210. Missing values were imputed by LOCF.

Arm/Group Title	Single Arm - Norspan Patch (Buprenorphine)
Arm/Group Description	This study is single arm for Norspan(buprenorphine) patch. Treatment with NORSPAN Ò will be started from 5 μg/h (1 patch a week) for 2 weeks, and proper titration (up-titration) will be allowed at visit 2(wk 2) and at visit 3(wk 4) according to the investigator's decision. The up-titration will be considered by investigator's judgement as follows; (1) if the rescue medication was used more than 2 times per day, on average or (2) based on the daily average NRS(Numeric Rating Scale), if the NRS was changed to worsen since the previous visit, (3) Investigator's judgement by considering any titration needed situation (e.g. dose, frequency of rescue medication).
Measure Participants	210
Very much improved	16 6.6%
Much improved	63 26.1%
Minimally improved	55 22.8%
No change	68 28.2%
Minimally worse	8 3.3%
Much worse	0 0%
Very much worse	0 0%

6. Secondary Outcome

Title	Patients Global Impression og Change(PGIC)
Description	Number of clinician with categorical change in overall status. PGIC: a participant-rated instrument assessing change in patient's overall status from baseline, on a scale ranging from 1 (very much improved) to 7 (very much worse).
Time Frame	8 week

Outcome Measure Data

Analysis Population Description

FAS set: 210. Missing values were imputed by LOCF.

Arm/Group Title	Single Arm - Norspan Patch (Buprenorphine)
Arm/Group Description	This study is single arm for Norspan(buprenorphine) patch. Treatment with NORSPAN Ò will be started from 5 μg/h (1 patch a week) for 2 weeks, and proper titration (up-titration) will be allowed at visit 2(wk 2) and at visit 3(wk 4) according to the investigator's decision. The up-titration will be considered by investigator's judgement as follows; (1) if the rescue medication was used more than 2 times per day, on average or (2) based on the daily average NRS(Numeric Rating Scale), if the NRS was changed to worsen since the previous visit, (3) Investigator's judgement by considering any titration needed situation (e.g. dose, frequency of rescue medication).
Measure Participants	210
Very much improved	12 5%
Much improved	60 24.9%
Minimally improved	57 23.7%
No change	71 29.5%
Minimally worse	10 4.1%
Much worse	0 0%
Very much worse	0 0%

Adverse Events

Time Frame	8 weeks
Arm/Group Title	Norspan Patch (Buprenorphine)
Arm/Group Description	Trade name is Norspan. Buprenorphine 5μg/h, 10 μg/h, 20 μg/h patches will be used (4 patches a box). Patch will be administered every 7th day. Buprenorphine: 8weeks treatment with Norspan®(Buprenorphine)
All Cause Mortality
	Norspan Patch (Buprenorphine)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Norspan Patch (Buprenorphine)
	Affected / at Risk (%)	# Events
Total	1/241 (0.4%)
Musculoskeletal and connective tissue disorders
Lumbar vertebral fracture	1/241 (0.4%)	1
Other (Not Including Serious) Adverse Events
	Norspan Patch (Buprenorphine)
	Affected / at Risk (%)	# Events
Total	143/241 (59.3%)
Cardiac disorders
Palpitations	2/241 (0.8%)	2
Ear and labyrinth disorders
Tinnitus	1/241 (0.4%)	1
Eye disorders
Lacrimal disorder	1/241 (0.4%)	1
Gastrointestinal disorders
Nausea	71/241 (29.5%)	77
Vomiting	35/241 (14.5%)	36
Constipation	7/241 (2.9%)	7
Abdominal pain upper	3/241 (1.2%)	3
Dry mouth	2/241 (0.8%)	2
Dyspepsia	2/241 (0.8%)	2
Abdominal discomfort	1/241 (0.4%)	1
Diarrhoea	1/241 (0.4%)	1
Lip swelling	1/241 (0.4%)	1
General disorders
Chills	2/241 (0.8%)	2
Chest discomfort	1/241 (0.4%)	1
Cyst	1/241 (0.4%)	1
Face oedema	1/241 (0.4%)	1
Feeling hot	1/241 (0.4%)	1
General physical health deterioration	1/241 (0.4%)	1
Pain	1/241 (0.4%)	1
Thirst	1/241 (0.4%)	1
Injury, poisoning and procedural complications
Lumbar vertebral fracture	1/241 (0.4%)	1
Metabolism and nutrition disorders
Decreased appetite	2/241 (0.8%)	2
Polydipsia	2/241 (0.8%)	2
Musculoskeletal and connective tissue disorders
Muscular weakness	1/241 (0.4%)	1
Musculoskeletal pain	1/241 (0.4%)	1
Sensation of heaviness	1/241 (0.4%)	1
Nervous system disorders
Dizziness	50/241 (20.7%)	52
Headache	14/241 (5.8%)	14
Somnolence	6/241 (2.5%)	7
Lethargy	2/241 (0.8%)	2
Paraesthesia	1/241 (0.4%)	1
Psychiatric disorders
Insomnia	3/241 (1.2%)	3
Sleep disorder	2/241 (0.8%)	2
Anxiety	1/241 (0.4%)	1
Renal and urinary disorders
Dysuria	2/241 (0.8%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/241 (0.4%)	1
Productive cough	1/241 (0.4%)	1
Skin and subcutaneous tissue disorders
Pruritus	22/241 (9.1%)	24
Erythema	2/241 (0.8%)	2
Blister	1/241 (0.4%)	1
Rash	1/241 (0.4%)	1
Vascular disorders
Flushing	1/241 (0.4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.