Prednisone Timed-Release Tablet (TRT) Study: Modified-Release (MR) Formulation of Prednisone Compared to Standard Immediate-Release (IR) Prednisone in Participants With Rheumatoid Arthritis

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00146640
• Collaborator: (none)
• Enrollment: 288
• Locations: 24
• Arms: 2
• Actual Duration (Months): 29
• Patients Per Site: 12
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The objective of this study is to investigate if low doses of prednisone MR formulation, given at night and, with active drug release at 2 am, are more effective in controlling joint stiffness, and other disease symptoms of rheumatoid arthritis than standard IR prednisone given in the morning.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: MR Prednisone; Drug: IR Prednisone; Drug: Placebo - MR Prednisone; Drug: Placebo - IR Prednisone	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 288 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A New Timed-Release Tablet Formulation of Prednisone Compared to Standard Prednisone in Patients With Rheumatoid Arthritis- A Randomized, Multi-Centre, Double-Blind, Active Controlled Study With Open Extension on the New Drug Only
• Actual Study Start Date: Aug 31, 2004
• Actual Primary Completion Date: Jan 31, 2007
• Actual Study Completion Date: Jan 31, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MR Prednisone Participants will receive MR prednisone at bed time and placebo matching to IR prednisone in the morning. Total duration of double blind treatment will be 12 weeks.	Drug: MR Prednisone; Participants will receive tablets containing MR prednisone (to achieve the appropriate dose of 3-10 milligrams [mg] prednisone per day) at bed time.; Drug: Placebo - IR Prednisone; Participants will receive placebo matching to IR prednisone tablet in the morning.
Active Comparator: IR Prednisone Participants will receive IR prednisone in the morning and placebo matching to MR prednisone at bed time. Total duration of double blind treatment will be 12 weeks.	Drug: IR Prednisone; Participants will receive tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning.; Drug: Placebo - MR Prednisone; Participants will receive placebo matching to MR prednisone tablet at bed time.

Outcome Measures

Primary Outcome Measures

1. Relative Change From Baseline in Duration of Morning Stiffness at Week 12 [Baseline, Week 12]

   Duration of morning stiffness was defined as the time elapsed (in minutes) between the time of usual awakening (even if not in the morning) and the time the participant was able to resume normal activities without stiffness. Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.

Secondary Outcome Measures

1. Relative Change From Baseline in 28-Joint Disease Activity Score (DAS28) at Week 12 [Baseline, Week 12]

   DAS28 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 28 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). Total DAS28 score range from 0 to approximately 10. DAS28 less than or equal to (≤) 3.2 = low disease activity, DAS28 greater than (>) 3.2 to 5.1 = moderate to high disease activity, and DAS28 >5.1 = severe disease activity. Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.

2. Percentage of Participants With Recurrence of Joint Stiffness at Week 12 [Week 12]

   Participants recorded the status of recurrence of joint stiffness (Yes/No) in diary data. Percentage of participants who selected Yes for recurrence of joint stiffness, are reported.

3. Relative Change From Baseline in Pain Intensity at Week 12 [Baseline, Week 12]

   Participants assessed pain intensity on a 100 millimeter (mm) visual analog scale (VAS), where 0 mm = no pain, 100 mm = worst pain. Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.

4. Relative Change From Baseline in Quality of Sleep at Week 12 [Baseline, Week 12]

   Participants assessed quality of sleep on a 100 mm VAS, where 0 mm = very good, 100 mm = very bad. Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.

5. Relative Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 [Baseline, Week 12]

   HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.

6. Relative Change From Baseline in Short-Form 36 (SF36) Mental Component Score (MCS) at Week 12 [Baseline, Week 12]

   SF-36 is a standardized survey evaluating 8 domains of functional health and wellbeing: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a domain was an average of the individual question scores, which were scaled 0-100 (100=highest level of functioning). Score from mental health, role emotional, social functioning, and vitality domains were averaged to calculate MCS. Total score range for MCS was 0-100 (100=highest level of mental functioning). Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.

7. Relative Change From Baseline in SF36 Physical Component Score (PCS) at Week 12 [Baseline, Week 12]

   SF-36 is a standardized survey evaluating 8 aspects of functional health and wellbeing: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a domain was an average of the individual question scores, which were scaled 0-100 (100=highest level of functioning). Score from physical function, role physical, bodily pain, and general health domains were averaged to calculate PCS. Total score range for PCS was 0-100 (100=highest level of physical functioning). Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Active disease (inflammatory signs, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP])

• Stable condition

• Stable basic treatments

• Morning stiffness on previous treatment with standard prednisone (below or equal to 10 mg per day) greater than or equal to (>/=) 45 minutes

Exclusion Criteria:

• All contra-indications for glucocorticoids

• Pregnancy

• Concomitant treatment with biologics

• Intra-articular injections or synovectomy within the previous 4 months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Aachen		Germany
2	Research Site	Bad Kreuznach		Germany
3	Research Site	Berlin		Germany
4	Research Site	Dresden		Germany
5	Research Site	Düsseldorf		Germany
6	Research Site	Erlangen		Germany
7	Research Site	Frankfurt/Main		Germany
8	Research Site	Hamburg		Germany
9	Research Site	Hannover		Germany
10	Research Site	Jena		Germany
11	Research Site	Köln		Germany
12	Research Site	Leipzig		Germany
13	Research Site	München		Germany
14	Research Site	Ratingen		Germany
15	Research Site	Rostock		Germany
16	Research Site	Bialystok		Poland
17	Research Site	Katowice		Poland
18	Research Site	Kraków		Poland
19	Research Site	Lublin		Poland
20	Research Site	Poznan		Poland
21	Research Site	Sopot		Poland
22	Research Site	Torun		Poland
23	Research Site	Warszawa		Poland
24	Research Site	Wroclaw		Poland

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT00146640
• Other Study ID Numbers: EMR 62215-003
• First Posted: Sep 7, 2005
• Last Update Posted: Jul 3, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by Merck KGaA, Darmstadt, Germany: active disease; morning stiffness of joints; nighttime application of prednisone; modified release prednisone
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Prednisone

Study Results

Participant Flow

Arm/Group Title	MR Prednisone	IR Prednisone
Arm/Group Description	Participants received tablets containing modified-release (MR) prednisone (to achieve the appropriate dose of 3-10 milligrams [mg] prednisone per day) at bed time and placebo matching to immediate-release (IR) prednisone tablet in the morning. Total duration of double blind treatment was 12 weeks.	Participants received tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning and placebo matching to MR prednisone tablet at bed time. Total duration of double blind treatment was 12 weeks.
Period Title: Overall Study
STARTED	144	144
COMPLETED	121	130
NOT COMPLETED	23	14

Baseline Characteristics

Arm/Group Title	MR Prednisone	IR Prednisone	Total
Arm/Group Description	Participants received tablets containing MR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) at bed time and placebo matching to IR prednisone tablet in the morning. Total duration of double blind treatment was 12 weeks.	Participants received tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning and placebo matching to MR prednisone tablet at bed time. Total duration of double blind treatment was 12 weeks.	Total of all reporting groups
Overall Participants	144	144	288
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.6 (11.2)	55.4 (11.4)	55.0 (11.3)
Sex: Female, Male (Count of Participants)
Female	125 86.8%	122 84.7%	247 85.8%
Male	19 13.2%	22 15.3%	41 14.2%

Outcome Measures

1. Primary Outcome

Title	Relative Change From Baseline in Duration of Morning Stiffness at Week 12
Description	Duration of morning stiffness was defined as the time elapsed (in minutes) between the time of usual awakening (even if not in the morning) and the time the participant was able to resume normal activities without stiffness. Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Arm/Group Title	MR Prednisone	IR Prednisone
Arm/Group Description	Participants received tablets containing MR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) at bed time and placebo matching to IR prednisone tablet in the morning. Total duration of double blind treatment was 12 weeks.	Participants received tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning and placebo matching to MR prednisone tablet at bed time. Total duration of double blind treatment was 12 weeks.
Measure Participants	125	129
Mean (Standard Deviation) [percent change]	-22.7 (89.1)	-0.4 (89.0)

2. Secondary Outcome

Title	Relative Change From Baseline in 28-Joint Disease Activity Score (DAS28) at Week 12
Description	DAS28 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 28 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). Total DAS28 score range from 0 to approximately 10. DAS28 less than or equal to (≤) 3.2 = low disease activity, DAS28 greater than (>) 3.2 to 5.1 = moderate to high disease activity, and DAS28 >5.1 = severe disease activity. Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Arm/Group Title	MR Prednisone	IR Prednisone
Arm/Group Description	Participants received tablets containing MR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) at bed time and placebo matching to IR prednisone tablet in the morning. Total duration of double blind treatment was 12 weeks.	Participants received tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning and placebo matching to MR prednisone tablet at bed time. Total duration of double blind treatment was 12 weeks.
Measure Participants	136	137
Mean (95% Confidence Interval) [percent change]	-9.03	-12.30

3. Secondary Outcome

Title	Percentage of Participants With Recurrence of Joint Stiffness at Week 12
Description	Participants recorded the status of recurrence of joint stiffness (Yes/No) in diary data. Percentage of participants who selected Yes for recurrence of joint stiffness, are reported.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Arm/Group Title	MR Prednisone	IR Prednisone
Arm/Group Description	Participants received tablets containing MR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) at bed time and placebo matching to IR prednisone tablet in the morning. Total duration of double blind treatment was 12 weeks.	Participants received tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning and placebo matching to MR prednisone tablet at bed time. Total duration of double blind treatment was 12 weeks.
Measure Participants	119	127
Number [percentage of participants]	47 32.6%	43 29.9%

4. Secondary Outcome

Title	Relative Change From Baseline in Pain Intensity at Week 12
Description	Participants assessed pain intensity on a 100 millimeter (mm) visual analog scale (VAS), where 0 mm = no pain, 100 mm = worst pain. Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Arm/Group Title	MR Prednisone	IR Prednisone
Arm/Group Description	Participants received tablets containing MR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) at bed time and placebo matching to IR prednisone tablet in the morning. Total duration of double blind treatment was 12 weeks.	Participants received tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning and placebo matching to MR prednisone tablet at bed time. Total duration of double blind treatment was 12 weeks.
Measure Participants	141	143
Mean (95% Confidence Interval) [percent change]	-8.57	-6.53

5. Secondary Outcome

Title	Relative Change From Baseline in Quality of Sleep at Week 12
Description	Participants assessed quality of sleep on a 100 mm VAS, where 0 mm = very good, 100 mm = very bad. Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Arm/Group Title	MR Prednisone	IR Prednisone
Arm/Group Description	Participants received tablets containing MR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) at bed time and placebo matching to IR prednisone tablet in the morning. Total duration of double blind treatment was 12 weeks.	Participants received tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning and placebo matching to MR prednisone tablet at bed time. Total duration of double blind treatment was 12 weeks.
Measure Participants	141	143
Mean (95% Confidence Interval) [percent change]	4.63	0.13

6. Secondary Outcome

Title	Relative Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12
Description	HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Arm/Group Title	MR Prednisone	IR Prednisone
Arm/Group Description	Participants received tablets containing MR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) at bed time and placebo matching to IR prednisone tablet in the morning. Total duration of double blind treatment was 12 weeks.	Participants received tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning and placebo matching to MR prednisone tablet at bed time. Total duration of double blind treatment was 12 weeks.
Measure Participants	137	138
Mean (95% Confidence Interval) [percent change]	0.07	-4.7

7. Secondary Outcome

Title	Relative Change From Baseline in Short-Form 36 (SF36) Mental Component Score (MCS) at Week 12
Description	SF-36 is a standardized survey evaluating 8 domains of functional health and wellbeing: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a domain was an average of the individual question scores, which were scaled 0-100 (100=highest level of functioning). Score from mental health, role emotional, social functioning, and vitality domains were averaged to calculate MCS. Total score range for MCS was 0-100 (100=highest level of mental functioning). Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Arm/Group Title	MR Prednisone	IR Prednisone
Arm/Group Description	Participants received tablets containing MR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) at bed time and placebo matching to IR prednisone tablet in the morning. Total duration of double blind treatment was 12 weeks.	Participants received tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning and placebo matching to MR prednisone tablet at bed time. Total duration of double blind treatment was 12 weeks.
Measure Participants	114	117
Mean (95% Confidence Interval) [percent change]	10.63	18.08

8. Secondary Outcome

Title	Relative Change From Baseline in SF36 Physical Component Score (PCS) at Week 12
Description	SF-36 is a standardized survey evaluating 8 aspects of functional health and wellbeing: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a domain was an average of the individual question scores, which were scaled 0-100 (100=highest level of functioning). Score from physical function, role physical, bodily pain, and general health domains were averaged to calculate PCS. Total score range for PCS was 0-100 (100=highest level of physical functioning). Relative (percent) change = ([value at Week 12 minus value at Baseline] divided by [value at baseline]) multiplied by 100.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Arm/Group Title	MR Prednisone	IR Prednisone
Arm/Group Description	Participants received tablets containing MR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) at bed time and placebo matching to IR prednisone tablet in the morning. Total duration of double blind treatment was 12 weeks.	Participants received tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning and placebo matching to MR prednisone tablet at bed time. Total duration of double blind treatment was 12 weeks.
Measure Participants	114	117
Mean (95% Confidence Interval) [percent change]	19.43	21.0

Adverse Events

Adverse Event Reporting Description	Among serious adverse events (SAEs), only data for total # affected by any SAE is available. Due diligence was done and all potential information sources have been exhausted; no further information could be retrieved. Hence, for SAEs the preferred term is reported as "Not Available" and System Organ Class as "General Disorders".
Arm/Group Title	MR Prednisone		IR Prednisone
Arm/Group Description	Participants received tablets containing MR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) at bed time and placebo matching to IR prednisone tablet in the morning. Total duration of double blind treatment was 12 weeks.		Participants received tablets containing IR prednisone (to achieve the appropriate dose of 3-10 mg prednisone per day) in the morning and placebo matching to MR prednisone tablet at bed time. Total duration of double blind treatment was 12 weeks.
All Cause Mortality
	MR Prednisone		IR Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	MR Prednisone		IR Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/144 (2.8%)		3/144 (2.1%)
General disorders
	4/144 (2.8%)		3/144 (2.1%)
Other (Not Including Serious) Adverse Events
	MR Prednisone		IR Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/144 (13.9%)		29/144 (20.1%)
Gastrointestinal disorders
Abdominal pain (upper)	5/144 (3.5%)		8/144 (5.6%)
Immune system disorders
Rheumatoid arthritis	11/144 (7.6%)		13/144 (9%)
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis	4/144 (2.8%)		8/144 (5.6%)

Limitations/Caveats

For SAEs, due diligence was done and all potential information sources have been exhausted, no further information could be retrieved apart from what is currently reported.

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.