Digital Ulcer of Scleroderma Clinical Trial
Official title:
Assessing and Comparing the Effect of Diltiazem Gel Versus Nitroglycerin Ointment in Healing Process of Scleroderma Digital Ulcers.
Digital ulcers are one of the most prevalent complications of scleroderma (systemic sclerosis). There can be found few surveys on effect of topical agents on healing process of the ulcers. Thus, the aim of this study is to assess and compare the effects of topical diltiazem on SSc digital ulcers versus topical nitroglycerin.
Introduction:
Systemic sclerosis, also named scleroderma (SSc), is an autoimmune connective tissue disease
associated with small vessels vasculopathy and collagen deposition in skin and other
internal organs [1, 2]. About 30-60 % of patients with limited and diffused type of
scleroderma developed by digital ulcers (DUs) in course of their disease [3]. Depending on
the sites of the ulcers, their pathophysiology is differed. The ones on distal parts of the
digits are related to ischemic changes based on Raynaud phenomenon, intimal
fibroproliferation, and thrombosis; while, the ones on bony prominences are mostly due to
microtrauma and following poor vascularization for its healing [4].
These ulcers can affect the quality of life of the patients mostly due to the pain and
difficulty in their healing [3]. Accordingly, several therapies have been introduced for
improving its healing process. Among them, nitroglycerin ointment was assessed to be an
effective topical agent on Raynaud phenomenon; however, there can be found only one study
assessing its effect on SSc digital ulcer, which was shown to be non significant [5-7].
Calcium channel blockers (CCB) such as diltiazem are also being used for Raynaud phenomenon
in scleroderma patients. Yet, some of their potential side effects such as peripheral edema,
hypotension, and headache limit the up titration of these classes of drugs [8]. Moreover,
their therapeutic effects on SSc digital ulcers are still being questionable. Only, one
clinical trial assessed the effect of nifedipine on ulcer healing, which resulted in
non-significant difference compared with placebo[7].
In addition to systemic form of CCBs, topical form of them such as diltiazem gel is also
being available. Previous studies introduced this form of diltiazem as a vasodilator,
mostly, for treatment of chronic anal fissure [9]. Comparing its effects with topical
nitrate for chronic anal fissures showed some controversies. Some studies resulted in no
significant difference between them; yet, the study by Ala et al, demonstrated that
diltiazem gel has superiority to nitroglycerin ointment [10, 11]. Another survey, in spite
of finding non- significant difference between these two agents in treatment of anal
fissure, gave priority to diltiazem gel because of headache induced by nitroglycerin
ointment [12].
As it can be inferred from previous studies, most of the medications used for scleroderma DU
healing are drugs applied for Raynaud phenomenon. In spite of the determined therapeutic
effects of such drugs on this phenomenon, their efficacy on healing of DUs is still being
obscured. Furthermore, because of the complications of systemic therapies and limitation in
their dose up titrating, topical agents are being preferred. However, there has not still
found an effective topical therapy for DU of scleroderma patients.
The effect of topical diltiazem as a vasodilator agent in treatment of anal fissure brings
to mind this idea that it may be also effective in healing of scleroderma DUs. In addition,
comparing the effect of diltiazem gel and topical nitrate in anal fissures, generally,
suggest the preference of the former. However, there can not be found any survey comparing
the effects of these two topical vasodilators in treatment of DU. Thus, in this study, we
aim to assess the effect of topical diltiazem on SSc digital ulcers and compare it by
topical nitroglycerin.
Material and Method:
A single blind case control study will be done on 90 scleroderma patients registered in
Tertiary Centers of rheumatology diseases of Shiraz University of Medical Sciences, Shiraz,
Iran. (The sample size was estimated using the formula of n = (Zα/2+Zβ)2 *
(p1(1-p1)+p2(1-p2)) / (p1-p2)2 [ Zα/2 is the critical value of the Normal distribution at
α/2 (for a confidence level of 95%, α is 0.05 and the critical value is 1.96), Zβ is the
critical value of the Normal distribution at β (for a power of 80%, β is 0.2 and the
critical value is 0.84) and p1 and p2 are the expected sample proportions of the two
groups]).
Inclusion Criteria:
The patients' scleroderma was diagnosed based on criteria of LeRoy[13]. The ones with ages
between 20-70 years old will be entered into the study. They, all, should have at least one
active digital ulcer.
Exclusion Criteria:
The cases with comorbid diseases such as diabetes, thyroid disease and cardiovascular
diseases will be excluded from the survey. Moreover, the patients who are smoker, opium
addict or alcohol abuser will also drop out of the study. In addition, the ones who received
inhaled or oral prostanoid in last 3 months, phosphodiesterase inhibitors except for
intermittent treatment of erectile dysfunction in last 1 month and the ones received
antibiotics 2 weeks prior to the study will, also, be excluded. The baseline hepatic
function test will be assessed and the cases with moderate to severe hepatic impairment or
increase in aminotransferase levels more than 3 will also be excluded from the survey.
The study design:
The patients will be divided into 3 groups; one control group consisting of 30 cases, and
two experimental groups with 30 patients in each of them. The control one (C) receiving
Vaseline ointment as placebo, the experimental group 1 (E1) which will receive diltiazem gel
(2%) applied on DUs two times daily and experimental group 2 (E2) treating by nitroglycerin
ointment (2%) applied two times daily for 8 weeks.
The number of the DUs and the mean diameter of all DUs will be measured in 3 groups at the
beginning and at the end of the study. Moreover, the site of the ulcers (fingertip, proximal
interphalangeal joint (PIP), distal interphalangeal joint (DIP), metacarpophalangeal joint
(MCP)) will be also taken into account and be submitted for each patient.
The number of new DUs developing during the study and the difference between mean diameters
of them will be compared between 3 groups. In addition, the difference in mean of DUs in
different sites will also be compared to see which site has more responsiveness to topical
therapeutic agents used in this survey.
Ethical Issues:
Informed consent to the entire protocol as well as forms compatible with Helsinki
Declaration was obtained from each patient. Ultimately, the ones who agreed to enroll will
be recruited for the study.
Statistical Analysis:
Data will be entered into SPSS 19. For comparing the number and mean difference of digital
ulcers' diameters between 3 groups and between different sites of the ulcer, one-way ANOVA
will be applied. In addition, Bonferroni test as the post hoc of ANOVA will be applied for
pairwise comparison of the groups. The significant p-value in all studies will be considered
<0.05.
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