Diltiazem Gel Versus Nitroglycerin Ointment in Healing Process of Scleroderma Digital Ulcers
Condition: Digital Ulcer of Scleroderma
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized; Skin Ulcer; Ulcer
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Diltiazem Gel 2%; Nitroglycerin Ointment 2%; Vaseline
Intervention type(s): Drug; Drug; Drug
Intervention description(s): This a topical agent which will be applied on digital ulcers by scleroderma patients.; This a topical agent which will be applied on digital ulcers by scleroderma patients.; This is used as the topical placebo agent.
Other intervention name(s): DILTIGEL; NITROCARD
Intervention MeSH terms: Diltiazem; Nitroglycerin; Petrolatum
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Scleroderma; Diltiazem; Nitroglycerin; Topical