Efficacy Study of PDE-5 Inhibitor and Calcium Channel Inhibitor for the Treatment of Secondary Raynaud Phenomenon

• Sponsor: Seoul National University Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01280266
• Collaborator: Dong-A Pharmaceutical Co., Ltd. (Industry)
• Enrollment: 29
• Location: 1
• Arms: 2
• Duration (Months): 5
• Patients Per Site Per Month: 5.8

Study Details

Study Description

Brief Summary

The prevalence of Raynaud phenomenon (RP), a reversible vaso-constriction with skin discoloration, is 5-10% in general population. Often conventional measures such as warming up or minimizing exposure to cold are not enough and many patients require treatment with a vasodilator therapy. A recent study showed a good efficacy and safety profile of sildenafil, a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in RP.

Here, the investigators aim to examine the efficacy and safety of Udenafil, a newer PDE5 inhibitor, as compared to amlodipine, a well known calcium channel blocker, in the treatment of secondary RP in Korean patients.

Condition or Disease	Intervention/Treatment	Phase
Raynaud Phenomenon	Drug: Udenafil or Amlodipine	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Comparison of Phosphodiesterase-5 Inhibitor and Calcium Channel Inhibitor for the Treatment of Secondary Raynaud Phenomenon, Double Blind, Randomized, Cross-over Trial
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Amlodipine-Udenafil (AU) arm Amlodipine 10mg PO QD for 4 weeks, washout period, then Udenafil 100mg PO QD for 4 weeks	Drug: Udenafil or Amlodipine; Amlodipine 10mg daily then Udenafil 100 mg daily OR Udenafil 100 mg daily then Amlodipine 10mg daily
Experimental: Udenafil-Amlodipine (UA) arm Udenafil 100mg PO QD for 4 weeks, washout period, then Amlodipine 10mg PO QD for 4 weeks	Drug: Udenafil or Amlodipine; Amlodipine 10mg daily then Udenafil 100 mg daily OR Udenafil 100 mg daily then Amlodipine 10mg daily

Outcome Measures

Primary Outcome Measures

1. RP Attacks Per Day [baselin and 4 weeks]

   Change in RP frequency after amlodipine and udenafil number of RP attack per day 0 -- unlimited.

Secondary Outcome Measures

1. Change in Raynaud's Condition Score (RCS) [baseline and 4 weeks]

   change in the RCS. RCS combines daily activty, frequency, duration and severity as well as impact of RP attack (Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon, Merkel et al,Arthritis Rheum. 2002 Sep;46(9):2410-20). Range 0-10 ordinal scale 0..good 10.. bad

2. Change in the RP Duration [baseline and 4 weeks]

   Change in the average RP duration in minutes (min) per attack. 0 -- unlimited

3. Change in Health Assessment Questionnaire (HAQ) [0 and 4 weeks]

   Ordinal scale 0-10 0 good 10 bad

4. Change in Physician's Global Assessment on Visual Analogue Scale (VAS) [at 0 (baseline) and 4 weeks (after treatment)]

   Physician's global assessment (PGA) on VAS assesses the overall condition of the patient. The scale ranges from 0 - 10, with 0 being good and 10 bad. As such, change in the GPA measures the change in the patient's condition from the baseline. negative value (decrease in value) means improvement.

5. Change in Digital Ulcer Number [baseline and 4 weeks]

   0 - unlimited. Number of digital ulcers in all fingers are counted by the investigators and recorded at each visit. The number of ulcers in all fingers indirectly reflect the extent of critical ischemia. As such. the decrease in digital ulcer number reflects positive response to treatment (=better blood flow), whereas the increase ulcer numbers indicates worsening finger ischemia from baseline.

6. Change in Peak Systolic Flow (cm/Sec) [baseline and 4 weeks]

   Change in digital artery flow velocity in proper palmar digital artery in cm/sec. 0-unlimited

7. Time-averaged Peak Velocity (cm/Sec) [baseline and 4 weeks]

   changes in the averaged blood flow (Time-averaged peak velocity) Blood flow in cm/sec 0 - unlimited.

8. Dorsal-digital-difference. [baseline and 4 weeks]

   The temperature difference between finger tips and dorsum of same hand. range 0 - unlimited in degree celcius.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• secondary Raynaud's phenomenon

Exclusion Criteria:

• primary raynaud phenomenon

• active infection

• hypersensitivity to PDE5 inhibitor or Calcium Chanel Blocker (CCB)

• elevated AST/ALT (3 times above the upper normal limit)

• severe renal failure

• patients on nitrite or nitric oxide (NO) donor treatment

• recent history of cerebrovascular accidents, acute myocardial infarction, or coronary artery bypass surgery

• hypotension (less than 90/50 mmHg) or uncontrolled hypertension

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Seoul National University Hospital	Seoul		Korea, Republic of	110-744

Sponsors and Collaborators

• Seoul National University Hospital
• Dong-A Pharmaceutical Co., Ltd.

Investigators

• Principal Investigator: Eun Bong Lee, MD PhD, professor of Seoul National University College of Medicine
• Study Director: Eun Young Lee, MD PhD, Assistant professor, Seoul National University College of Medicine
• Study Director: Jin Kyun Park, MD, Seoul National University Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eun Bong Lee, Direct, Division of Rheumatology, Seoul National University Hospital
• ClinicalTrials.gov Identifier: NCT01280266
• Other Study ID Numbers: RaynaudSNUH
• First Posted: Jan 20, 2011
• Last Update Posted: Dec 11, 2012
• Last Verified: Dec 1, 2012

• Keywords provided by Eun Bong Lee, Direct, Division of Rheumatology, Seoul National University Hospital: Pathological Conditions; Signs and Symptoms; Blood circulation
• Additional relevant MeSH terms: Raynaud Disease; Amlodipine; Udenafil

Study Results

Participant Flow

Recruitment Details	Recruitment begin Jan 13 2011 until Mar 15 2011. Location: Rheumatology outpatient clinic at Seoul National University Hospital, Seoul, Korea.
Pre-assignment Detail	30 Patients were initially recruited, but an error occurred in obtaining informed consent and this one was withdrawn.

Arm/Group Title	Amlodipine-Udenafil (AU) Arm	Udenafil-Amlodipine (UA) Arm
Arm/Group Description	Amlodipine 10mg PO QD for 4 weeks, washout period for 1week, then Udenafil 100mg PO QD for 4 weeks.	Udenafil 100mg PO QD for 4 weeks, washout period for 1 week, then Udenafil 10mg PO QD for 4 weeks.
Period Title: First Intervention (Week 1-4)
STARTED	15	14
COMPLETED	14	12
NOT COMPLETED	1	2
Period Title: First Intervention (Week 1-4)
STARTED	14	12
COMPLETED	14	12
NOT COMPLETED	0	0
Period Title: First Intervention (Week 1-4)
STARTED	14	12
COMPLETED	14	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Amlodipine-Udenafil (AU) Arm	Udenafil-Amlodipine (UA) Arm	Total
Arm/Group Description	Amlodipine first, then Udenafil	Udenafil first, then Amlodipine	Total of all reporting groups
Overall Participants	14	12	26
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	12 100%	26 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.6 (14.0)	52.3 (10.3)	50.9 (12.3)
Sex: Female, Male (Count of Participants)
Female	13 92.9%	11 91.7%	24 92.3%
Male	1 7.1%	1 8.3%	2 7.7%
Region of Enrollment (participants) [Number]
Korea, Republic of	14 100%	12 100%	26 100%
Disease subtype (participant) [Number]
Localized systemic sclerosis (SSc)	1	2	3
diffuse SSc	10	7	17
Mixed connective tissue disease	1	2	3
Sjogren's disease	2	1	3
RP duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.8 (8.7)	5.6 (2.3)	7.3 (6.6)
Prior use of vasodilator (Participant) [Number]
calcium channel blocker	1	4	5
angiotensin receptor blocker	2	0	2
Pentyxifylline	1	1	2
No prior use	10	7	17

Outcome Measures

1. Primary Outcome

Title	RP Attacks Per Day
Description	Change in RP frequency after amlodipine and udenafil number of RP attack per day 0 -- unlimited.
Time Frame	baselin and 4 weeks

Outcome Measure Data

Analysis Population Description

14 patients in UA arm + 12 patients in AU arm

Arm/Group Title	Amlodipine	Udenafil
Arm/Group Description	Changes in RP attacks per day during amlodipine 10 mg orally per day	Changes in RP attacks per day during udenafil 100mg orally per day
Measure Participants	26	26
Mean (Standard Deviation) [attacks per day]	-0.5 (1.4)	-0.5 (0.9)

2. Secondary Outcome

Title	Change in Raynaud's Condition Score (RCS)
Description	change in the RCS. RCS combines daily activty, frequency, duration and severity as well as impact of RP attack (Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon, Merkel et al,Arthritis Rheum. 2002 Sep;46(9):2410-20). Range 0-10 ordinal scale 0..good 10.. bad
Time Frame	baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine	Udenafil
Arm/Group Description	Changes in RPS during amlodipine 100 mg orally per day	Changes in RPS during udenafil 10 mg orally per day
Measure Participants	26	26
Mean (Standard Deviation) [units on a scale]	-0.5 (1.5)	-0.3 (1.0)

3. Secondary Outcome

Title	Change in the RP Duration
Description	Change in the average RP duration in minutes (min) per attack. 0 -- unlimited
Time Frame	baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine	Udenafil
Arm/Group Description	Drug: amlodipine 100 mg p.o. per day	Drug: udenafil 10 mg p.o. per day
Measure Participants	26	26
Mean (Standard Deviation) [min per attack]	-1.1 (5.9)	-1.4 (11.4)

4. Secondary Outcome

Title	Change in Health Assessment Questionnaire (HAQ)
Description	Ordinal scale 0-10 0 good 10 bad
Time Frame	0 and 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine	Udenafil
Arm/Group Description	Drug: amlodipine 100 mg p.o. per day	Drug: udenafil 10 mg p.o. per day
Measure Participants	26	26
Mean (Standard Deviation) [units on a scale]	0.1 (0.4)	-0.1 (0.3)

5. Secondary Outcome

Title	Change in Physician's Global Assessment on Visual Analogue Scale (VAS)
Description	Physician's global assessment (PGA) on VAS assesses the overall condition of the patient. The scale ranges from 0 - 10, with 0 being good and 10 bad. As such, change in the GPA measures the change in the patient's condition from the baseline. negative value (decrease in value) means improvement.
Time Frame	at 0 (baseline) and 4 weeks (after treatment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine	Udenafil
Arm/Group Description	Drug: amlodipine 100 mg p.o. per day	Drug: udenafil 10 mg p.o. per day
Measure Participants	26	26
Mean (Standard Deviation) [units on a scale]	-0.9 (1.4)	-1.5 (1.6)

6. Secondary Outcome

Title	Change in Digital Ulcer Number
Description	0 - unlimited. Number of digital ulcers in all fingers are counted by the investigators and recorded at each visit. The number of ulcers in all fingers indirectly reflect the extent of critical ischemia. As such. the decrease in digital ulcer number reflects positive response to treatment (=better blood flow), whereas the increase ulcer numbers indicates worsening finger ischemia from baseline.
Time Frame	baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine	Udenafil
Arm/Group Description	Drug: amlodipine 100 mg p.o. per day	Drug: udenafil 10 mg p.o. per day
Measure Participants	26	26
Mean (Standard Deviation) [Digital ulcers]	0.1 (0.4)	0.1 (0.3)

7. Secondary Outcome

Title	Change in Peak Systolic Flow (cm/Sec)
Description	Change in digital artery flow velocity in proper palmar digital artery in cm/sec. 0-unlimited
Time Frame	baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine	Udenafil
Arm/Group Description	Drug: amlodipine 100 mg p.o. per day	Drug: udenafil 10 mg p.o. per day
Measure Participants	26	26
Mean (Standard Deviation) [cm/sec]	-19.9 (145.9)	63.2 (170.2)

8. Secondary Outcome

Title	Time-averaged Peak Velocity (cm/Sec)
Description	changes in the averaged blood flow (Time-averaged peak velocity) Blood flow in cm/sec 0 - unlimited.
Time Frame	baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine	Udenafil
Arm/Group Description	Drug: amlodipine 100 mg p.o. per day	Drug: udenafil 10 mg p.o. per day
Measure Participants	26	26
Mean (Standard Deviation) [cm/sec]	-17.3 (98.6)	33.4 (123)

9. Secondary Outcome

Title	Dorsal-digital-difference.
Description	The temperature difference between finger tips and dorsum of same hand. range 0 - unlimited in degree celcius.
Time Frame	baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine	Udenafil
Arm/Group Description	Drug: amlodipine 100 mg p.o. per day	Drug: udenafil 10 mg p.o. per day
Measure Participants	26	26
Mean (Standard Deviation) [degree celcius.]	-0.7 (3.2)	-1.4 (3.3)

Adverse Events

Time Frame	During 8 weeks while taking a study drug.
Adverse Event Reporting Description	As a cross over trial, study participants received both amlodipine and udenafil following each other.
Arm/Group Title	Amlodipine		Udenafil
Arm/Group Description	Adverse effects observed while taking amlodipine in both study arms		Adverse effects observed while taking udenafil in both study arms
All Cause Mortality
	Amlodipine		Udenafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Amlodipine		Udenafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		2/26 (7.7%)
General disorders
Facial edema	0/26 (0%)	0	1/26 (3.8%)	1
Musculoskeletal and connective tissue disorders
Myalgia	0/26 (0%)	0	1/26 (3.8%)	1
Other (Not Including Serious) Adverse Events
	Amlodipine		Udenafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/26 (53.8%)		19/26 (73.1%)
Congenital, familial and genetic disorders
Zoster	1/26 (3.8%)	1	0/26 (0%)	0
Eye disorders
Blurred vision	2/26 (7.7%)	2	2/26 (7.7%)	2
General disorders
Facial flushing	8/26 (30.8%)	8	13/26 (50%)	13
Facial edema	4/26 (15.4%)	4	10/26 (38.5%)	10
Peripheral edema	4/26 (15.4%)	4	6/26 (23.1%)	6
Headache	3/26 (11.5%)	3	3/26 (11.5%)	3
Epistaxis	1/26 (3.8%)	1	0/26 (0%)	0
Dry mouth	1/26 (3.8%)	1	0/26 (0%)	0
Throat irritation	1/26 (3.8%)	1	0/26 (0%)	0
Nervous system disorders
Paresthesia	3/26 (11.5%)	3	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders
Pruritus	1/26 (3.8%)	1	2/26 (7.7%)	2

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.