Randomised Control Trial to Assess the Efficacy of Tadalafil in Raynaud's Phenomenon in Scleroderma
Condition: Raynaud Disease
MeSH terms: Raynaud Disease; Scleroderma, Systemic; Scleroderma, Diffuse
Study type: Interventional
Phase: Phase 3

Summary: 
      In this double-blinded, placebo-controlled, fixed-dose, study patients will be randomly
      assigned to take placebo or 20 mg tadalafil thrice weekly for 6 weeks. After 6 weeks a wash
      out period of 2 week will be observed and then the two groups will be switched over to
      receive the other drug. We planned a priori to include 20 patients. The concomitant
      medication for treatment of rheumatic disease remained unchanged during the whole study.
      Patient will undergo clinical and lab evaluation for organ damage for kidney and lungs. ECHO
      heart will be done at base line to assess the PAH and LV function and repeated at the end of
      the study. Blood pressure will be recorded at each visit. A physician unaware of the
      treatment group will record skin score and appearance of new cutaneous ulcers. The primary
      outcome variables will be frequency and duration of Raynauds attacks, evolution of trophic
      digital lesions and change in flow mediated dilatation of the brachial artery. Flow mediated
      dilatation of the brachial artery will be done at baseline 6 and 12 weeks.
    

Detailed description: 
      Introduction Raynaud's syndrome, which was first described by Maurice Raynaud in 1862, is
      defined as episodic cold or emotional stress-triggered ischemic vasospasms of the digital
      arteries and precapillary arterioles. This phenomenon affects 95% of the systemic sclerosis
      (SScl) patients and may lead to superficial ulcerations and in severe cases can even result
      in deep tissue necrosis with gangrene. Raynaud's phenomenon (RP) is symptom of a generalised
      vasculopathy in SScl, which eventually leads to a fibroproliferative arteriopathy. Pulmonary
      artery hypertension is one of many serious sequelae of this process. Nonpharmacological
      therapy includes avoidance of cold temperatures, emotional stress, and smoking.
      Pharmacological therapy with vasodilators such as calcium channel blockers, alpha adrenergic
      receptor blockers, or angiotensin II receptor antagonists and other agents has been used.
      Effects of treatments, however, are often inadequate.1 Sildenafil is a selective inhibitor of
      cGMP specific phosphodiesterase type 5. Besides its established effect in erectile
      dysfunction, sildenafil provides cGMP-dependent microvascular and macrovascular dilation and,
      furthermore, were recently shown to exhibit antiproliferative effects.2 There are a few
      studies in the literature on the efficacy of sildenafil in Raynaud's disease.3-5 It has been
      shown by these studies and a few case reports that sildenafil may be useful in RP. The
      limitation of sildenafil is its short t1/2 (4 hours). Tadalafil is more selective and longer
      acting (17 hours) analogue of sildenafil.6 These PDE 5 inhibitors have been shown to improve
      endothelial function in diabetic subjects and cold induced vasospasm.7 It is a well known
      fact that endothelial dysfunction is one of the major pathogenetic mechanisms in
      scleroderma8. There has been no randomised control trial on the efficacy of tadalafil in RP.
      There is one study that had shown beneficial effect of Tadalafil in cold induced
      vasoconstriction in pateints with Raynaud's phenomenon9. So we designed this study to assess
      the effect of tadalafil on Raynauds phenomenon and endothelial dysfunction in scleroderma. We
      hypothesise that the tadalafil improves the Raynaud's phenomenon and endothelial dysfunction
      in scleroderma patients and can act as a disease-modifying agent.

      Patients with systemic, scleroderma will be enrolled.

      Study Protocol In this double-blinded, placebo-controlled, fixed-dose, study patients will be
      randomly assigned to take placebo or 20 mg tadalafil thrice weekly for 6 weeks. After 6 weeks
      a wash out period of 2 week will be observed and then the two groups will be switched over to
      receive the other drug. We planned a priori to include 30 patients. The concomitant
      medication for treatment of rheumatic disease remained unchanged during the whole study.
      Patient will undergo clinical and lab evaluation for organ damage for kidney and lungs. ECHO
      heart will be done at base line to assess the PAH and LV function and repeated at the end of
      the study. Blood pressure will be recorded at each visit. A physician unaware of the
      treatment group will record skin score and appearance of new cutaneous ulcers. The primary
      outcome variables will be frequency and duration of Raynaud's attacks, evolution of trophic
      digital lesions and change in flow mediated dilatation of the brachial artery. Flow mediated
      dilatation of the brachial artery will be done at baseline 6 and 12 weeks.

      Clinical Evaluation Symptoms of Raynaud's phenomenon will be assessed by diary cards. When an
      attack occurred, patients immediately recorded the event and its duration in the diary. At
      the end of each day, patients gave an overall estimation of the last 24 hours, using a
      10-point Raynaud's Condition Score (0 points - subject felt not handicapped by Raynauds
      attacks; 10 points - subject felt extremely handicapped) validated as described elsewhere.
      Local Temperature will be recorded in a separate column in the diary daily.

      Assessment of cutaneous digital tip ulcers/ infarcts:

      The number and position of cutaneous digital tip ulcers or infarcts on any finger will be
      recorded. Data on both ulcers and infarcts will be collected.

      Health Assessment Questionnaire (HAQ):

      The HAQ is a self-administered instrument that measures physical disability in 8 domains of
      function: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activity. A
      visual analog scale (VAS) for pain is also part of the HAQ. The results for the 8 subscales,
      the composite disability score, and the pain measurement are each reported on a 0-3 scale.
      The HAQ has been used extensively in studies of rheumatoid arthritis and has also been
      validated in patients with scleroderma. Levels of circulating soluble markers of endothelial
      cell function, including soluble isoforms of endothelin 1 (ET-1), von Willebrand factor
      (vWF), and procollagen type I N-terminal propeptide (PINP) will be measured at 0 and 12 weeks
      Statistics Students T test will be applied to the continuous variables whereas chi square
      test will be applied to categorical variables.

      From an analysis of the daily record sheets, the Following will be calculated: (i) the total
      average daily duration of the attacks (TADDA), obtained by dividing the total duration in min
      of attacks during a given three -week interval (observation period) by the number of diary
      days; (ii) the average duration of a single attack (ADSA), by dividing the overall duration
      by the number of attacks during the observation period; (iii) the average daily frequency of
      the attacks (ADFA), by dividing the total number of attacks during the interval considered (3
      weeks) by the number of diary days; and (iv) the severity of the attacks, measured on a
      visual analogical scale; this will be designated the Raynaud's condition score (RCS) and will
      be calculated as the arithmetic average of the daily scores during the interval considered
      (3weeks).
    

Intervention name(s): Tadalafil
Intervention type(s): Drug
Intervention description(s): Tablets Tadalafil, 20 mg, alternate days, 6 weeks
Other intervention name(s): Tadalis
Intervention MeSH terms: Tadalafil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Raynaud disease; Scleroderma