Topical 10 % Nifedipine Versus 5% Sildenafil in Secondary Raynaud

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ClinicalTrials.gov Identifier: NCT03027674

Recruitment Status : Completed

First Posted : January 23, 2017

Last Update Posted : January 23, 2017

Sponsor:

Information provided by (Responsible Party):

Pontificia Universidad Catolica de Chile

Study Description

Brief Summary:

Objective: To compare the efficacy of topical 10% nifedipine versus 5% sildenafil in patients with secondary Raynaud's phenomenon (RP).

Methods: A randomized, double-blind, placebo-controlled pilot study took place in 10 patients with secondary RP. Topical 10% nifedipine on one hand and 5% sildenafil on the other hand were applied. The thumbs didn't receive any cream and served as a control group. The primary outcome was the improvement of blood flow and vessel diameter of the digital arteries measured by high frequency color Doppler ultrasound before and 1 hour after treatment.

Condition or disease	Intervention/treatment	Phase
Raynaud Phenomenon Due to Trauma Raynaud Disease System; Sclerosis Lupus Erythematosus, Systemic Dermatomyositis Ultrasound Therapy; Complications	Drug: 10% nifedipine cream Drug: 5% sildenafil cream	Early Phase 1

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Detailed Description:

Raynaud's phenomenon (RP) is an exaggerated vascular response characterized by at least biphasic change (pallor and cyanosis) in the skin color of the digits, induced by cold temperature or emotional stress, The prevalence varies from 3 to 5%. In primary RP, there is no evidence of a secondary cause and patients have a younger age at onset (between 15 and 30 years), whereas in secondary RP, patients are older and have a connective tissue diseases (CTD), such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), dermatomyositis (DM), Sjögren's syndrome and rheumatoid arthritis. In secondary RP there are endothelial dysfunction and intimal fibrosis that compromise capillary blood flow. The treatment includes maintaining warmth of the whole body, smoking cessation and avoiding cold exposure, sympathomimetic medications and emotional stress. When these measures fail, the first line drugs are calcium-channel blockers (CCBs), eg. nifedipine. If CCBs are ineffective or not tolerated, a phosphodiesterase type 5 inhibitor (PDE-5), eg. sildenafil, or a topical nitrate should be used alone or in combination with CCBs. Other drugs includes serotonin reuptake inhibitors, angiotensin receptor blockers and prostaglandins. Unfortunately, secondary RP in patients with CTD most often is refractory to standard therapies, becoming a therapeutic challenge for clinicians. Based on the pathophysiology, topical vasodilators may act as an adjuvant therapy. Several randomized trials have demonstrated the benefit of various forms of topical nitrates (eg. nitroglycerin). In relation to other topical agents, solid evidence is lacking. Color Doppler ultrasound is a noninvasive imaging method that allows observation with good definition of skin and deep planes, including vascularization in real time.

The aim of this study is to compare the efficacy of topical 10% nifedipine versus 5% sildenafil in patients with secondary RP using high-frequency color Doppler ultrasound Patients The inclusion criteria considered patients with secondary RP associated with a CTD diagnosed and under follow-up in the Department of Dermatology. Diagnosis of CTD was made according to the ACR classification criteria for SSc, the Mixed Connective Tissue Disease criteria proposed by Kasukawa et al, the Bohan and Peter DM criteria and the SLICC SLE criteria. The exclusion criteria were primary RP patients; concurrent infection of any digit; allergic reaction and current use of any CCB or PDE-5 inhibitor;, , pregnancy, hypo and hypertension, history of myocardial infarction, stroke, or life-threatening arrhythmia. All patients signed a written informed consent. The Ethics Committee of Pontificia Universidad Católica de Chile approved the study protocol.

Study design This prospective study was conducted in August 2016 (winter). After screening, patients who were being treated with a vasodilator were required to discontinue it for at least 24 hours before randomization. All patients were receiving immunosuppressive treatment for their underlying disease. Patient hands (right versus left) were randomized to treatment with topical sildenafil or nifedipine cream. The thumbs of both hands didn't receive any cream so that each subject served as her own control. Subjects were instructed to apply 5 grams of 10% nifedipine cream in one hand and 5 grams of 5% sildenafil cream to the opposite hand. Vinyl gloves were supplied to improve the absorption of the cream into the hand, leaving the thumb of both hands out of the glove without any cream.

Clinical assessments The temperature of the examination room was set at 19ºC (66ºF) for ≥ 30 min and all patients underwent a high-frequency color Doppler ultrasound examination before and 1 hour after the topical treatments. The same radiologist with extensive experience in dermatologic ultrasound, performed all sonographic examinations. The radiologist was blinded to the clinical data of the study and the senior dermatologist in charge of the supervision of the application of the topical treatments was blinded to the color Doppler ultrasound results. The ultrasound equipment was a Logic E9 XD Clear working with a high frequency (upper range 18 MHz) compact linear probe (General Electric Health Systems, Waukesha, WI). The ultrasound protocol included grey scale, color Doppler and spectral curve analysis of the arterial flow using the settings of the machine for studying skin and superficial structures. The ultrasound device automatically provided the values. The primary outcome was the improvement of blood flow in the digital arteries. For Doppler sonography, peak systolic velocity (PSV, cm/sec) and diameter (mm) were measured at the palmar proper digital (PPD) arteries (proximal phalanx level) of radial aspect of the index, middle and thumb fingers of both hands. Also, PSV and diameter were measured at the dorsal (PD) arterial arch of the proximal nail fold of the index, middle and thumb fingers of both hands. Immediate and late adverse effects were monitored in all patients until 3 months after the study.

Statistical analysis PSV of the PPD artery and PD arterial arch of the index and middle fingers were added for a total PSV. The diameter of the PPD artery and PD arterial arch of the index and middle fingers were added for a total diameter. Due to the low velocity ranges, the values of peak systolic velocities in cm/sec were transformed into mm/sec. Treatment efficacy was assessed by using the differences in digital artery blood flows (total PSV) and diameters (total diameter) at baseline (time [t] = 0) and after 60 minutes (t = 60). Difference in digital artery blood flow and the digital artery diameter was defined as (t = 0) minus (t = 60); thus, the efficacy of the treatment was reflected by a negative difference. In all cases, mean differences less than zero indicates that the study drug cream was effective; mean differences greater than or equal to zero indicates that the study drug cream was ineffective. The Wilcoxon signed-rank tests and paired t-tests were used to assess the changes in outcomes within the group before and after treatment as appropriate. All tests were performed using two-tailed probabilities and p ≤ 0.05 was considered statistically significant.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	10 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	"Color Doppler Ultrasound Comparison of Topical 10 % Nifedipine Versus 5% Sildenafil in Secondary Raynaud: A Randomized, Double-blind, Placebo-controlled Pilot Study"
Study Start Date :	August 2016
Actual Primary Completion Date :	August 2016
Actual Study Completion Date :	August 2016

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Raynaud phenomenon

Drug Information available for: Nifedipine Sildenafil Sildenafil citrate

Genetic and Rare Diseases Information Center resources: Dermatomyositis Systemic Scleroderma Polymyositis Idiopathic Inflammatory Myopathy

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: 10% nifedipine cream Patient hands (right versus left) were randomized to treatment with topical sildenafil or nifedipine cream. The thumbs of both hands didn't receive any cream so that each subject served as her own control. Subjects were instructed to apply 5 grams of 10% nifedipine cream in one hand and 5 grams of 5% sildenafil cream to the opposite hand. Vinyl gloves were supplied to improve the absorption of the cream into the hand, leaving the thumb of both hands out of the glove without any cream.	Drug: 10% nifedipine cream Topical treatment for Raynaud Other Name: Topical treatment for Raynaud
Active Comparator: 5% sildenafil cream Patient hands (right versus left) were randomized to treatment with topical sildenafil or nifedipine cream. The thumbs of both hands didn't receive any cream so that each subject served as her own control. Subjects were instructed to apply 5 grams of topical10% nifedipine cream in one hand and 5 grams of topical 5% sildenafil cream to the opposite hand. Vinyl gloves were supplied to improve the absorption of the cream into the hand, leaving the thumb of both hands out of the glove without any cream.	Drug: 5% sildenafil cream Topical treatment for Raynaud Other Name: Topical treatment for Raynaud

Arm

Intervention/treatment

Experimental: 10% nifedipine cream

Patient hands (right versus left) were randomized to treatment with topical sildenafil or nifedipine cream. The thumbs of both hands didn't receive any cream so that each subject served as her own control. Subjects were instructed to apply 5 grams of 10% nifedipine cream in one hand and 5 grams of 5% sildenafil cream to the opposite hand. Vinyl gloves were supplied to improve the absorption of the cream into the hand, leaving the thumb of both hands out of the glove without any cream.

Drug: 10% nifedipine cream

Topical treatment for Raynaud

Other Name: Topical treatment for Raynaud

Active Comparator: 5% sildenafil cream

Patient hands (right versus left) were randomized to treatment with topical sildenafil or nifedipine cream. The thumbs of both hands didn't receive any cream so that each subject served as her own control. Subjects were instructed to apply 5 grams of topical10% nifedipine cream in one hand and 5 grams of topical 5% sildenafil cream to the opposite hand. Vinyl gloves were supplied to improve the absorption of the cream into the hand, leaving the thumb of both hands out of the glove without any cream.

Drug: 5% sildenafil cream

Topical treatment for Raynaud

Other Name: Topical treatment for Raynaud

Outcome Measures

Primary Outcome Measures :

Improvement of blood flow in the digital arteries (peak systolic velocity ) of the dorsal arterial arch of the proximal nail fold of the index, middle and thumb fingers of both hands [ Time Frame: Outcome measure will be assessed the same day of the study and the data will be presented after the data is analyzed (12 weeks) ]
The peak systolic velocity peak is measured with Doppler sonography in centimeters/second

Secondary Outcome Measures :

Improvement of the diameter (mm) of the dorsal arterial arch of the proximal nail fold of the of the index, middle and thumb fingers of both hands. [ Time Frame: Outcome measure will be assessed the same day of the study and the data will be presented after the data is analyzed (12 weeks) ]
The diameter is measured with Doppler sonography in millimeters

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	13 Years to 99 Years (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

- Clinical diagnosis of secondary Raynaud´s phenomenon associated with a connective tissue disease

Exclusion Criteria:

Primary Raynaud´s phenomenon
Current infection of any digit
Known allergic reaction to calcium-channel blockers or phosphodiesterase type 5 inhibitor
Current use of calcium-channel blockers or phosphodiesterase type 5 inhibitors
Pregnancy
Hypotension or hypertension
History of myocardial infarction, stroke, or life-threatening arrhythmia.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03027674

Locations

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Chile
Department of Dermatology, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Santiago, RM, Chile, 7820436

Sponsors and Collaborators

Pontificia Universidad Catolica de Chile

Investigators

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Principal Investigator:	Cristian Vera-Kellet, MD	Connective Tissue Diseases Unit, Department of Dermatology Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

More Information

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Responsible Party:	Pontificia Universidad Catolica de Chile
ClinicalTrials.gov Identifier:	NCT03027674
Other Study ID Numbers:	16-234
First Posted:	January 23, 2017 Key Record Dates
Last Update Posted:	January 23, 2017
Last Verified:	January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Pontificia Universidad Catolica de Chile:


Raynaud Phenomena System; Sclerosis Lupus Erythematosus, Systemic	Ultrasound sildenafil Nifedipine

Additional relevant MeSH terms:

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Dermatomyositis Raynaud Disease Lupus Erythematosus, Systemic Scleroderma, Systemic Scleroderma, Diffuse Sclerosis Pathologic Processes Polymyositis Myositis Muscular Diseases Musculoskeletal Diseases Neuromuscular Diseases Nervous System Diseases Connective Tissue Diseases Skin Diseases	Peripheral Vascular Diseases Vascular Diseases Cardiovascular Diseases Autoimmune Diseases Immune System Diseases Nifedipine Sildenafil Citrate Vasodilator Agents Phosphodiesterase 5 Inhibitors Phosphodiesterase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Urological Agents Calcium Channel Blockers Membrane Transport Modulators

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