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Randomised Control Trial to Assess the Efficacy of Tadalafil in Raynaud's Phenomenon in Scleroderma

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ClinicalTrials.gov Identifier: NCT00626665
Recruitment Status : Completed
First Posted : February 29, 2008
Last Update Posted : March 22, 2013
Sponsor:
Information provided by (Responsible Party):
Vikas Agarwal, Sanjay Gandhi Postgraduate Institute of Medical Sciences

Tracking Information
First Submitted Date  ICMJE February 21, 2008
First Posted Date  ICMJE February 29, 2008
Last Update Posted Date March 22, 2013
Study Start Date  ICMJE December 2007
Actual Primary Completion Date April 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 28, 2008)
The primary outcome variables will be frequency and duration of Raynaud's attacks, evolution of trophic digital lesions [ Time Frame: 6 weeeks and 12 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2008)
change in flow mediated dilatation of the brachial artery [ Time Frame: 6 weeks and 12 weeks ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Randomised Control Trial to Assess the Efficacy of Tadalafil in Raynaud's Phenomenon in Scleroderma
Official Title  ICMJE Randomised Control Trial to Assess the Efficacy of Tadalafil in Raynaud's Phenomenon in Scleroderma
Brief 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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Raynaud Disease
Intervention  ICMJE Drug: Tadalafil
Tablets Tadalafil, 20 mg, alternate days, 6 weeks
Other Name: Tadalis
Study Arms  ICMJE Placebo Comparator: Placebo
One placebo tablet every alternate day for 6 weeks
Intervention: Drug: Tadalafil
Publications * Shenoy PD, Kumar S, Jha LK, Choudhary SK, Singh U, Misra R, Agarwal V. Efficacy of tadalafil in secondary Raynaud's phenomenon resistant to vasodilator therapy: a double-blind randomized cross-over trial. Rheumatology (Oxford). 2010 Dec;49(12):2420-8. doi: 10.1093/rheumatology/keq291. Epub 2010 Sep 12.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 29, 2008)
25
Original Actual Enrollment  ICMJE
 (submitted: February 28, 2008)
30
Actual Study Completion Date  ICMJE April 2008
Actual Primary Completion Date April 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female subjects between the ages of 18 years and 60 years will be selected for the study if they have a clinical diagnosis of Raynaud's phenomenon secondary to systemic sclerosis (scleroderma). Raynaud's phenomenon is defined as a history of cold sensitivity associated with colour changes of cyanosis or pallor, as well as a history of at least 4 attacks per week during two pre-trial period even with treatment with other vasodilators. The diagnosis of scleroderma is defined by the American College of Rheumatology (ACR) criteria or by the presence of at least 3 of the 5 features of the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias).

Exclusion Criteria:

Patients will be excluded if they have:

  • Symptomatic orthostatic hypotension
  • Evidence of current malignancy
  • History of sympathectomy
  • Upper extremity deep vein thrombosis or lymphedema within 3 months
  • Recent surgical procedure requiring general anesthesia
  • AMI, unstable angina, strokes and TIA within the past three months
  • Smoking
  • Use of any investigational drug within 30 days of the study sessions
  • Use of medications that might interfere with tadalafil like nitrates and alpha adrenergic blockers that have vasoactive effects, and patients taking potent inhibitors of CYP3A4 such as ritonavir, ketoconazole, and itraconazole, erythromycin, itraconazole, and grapefruit juice
  • Patients taking alcohol
  • Patients with bleeding disorders
  • Significant active peptic ulceration
  • Current pregnancy
  • Current breast-feeding
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00626665
Other Study ID Numbers  ICMJE A-15;PGI/DM/EC/40/7/11/07
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Vikas Agarwal, Sanjay Gandhi Postgraduate Institute of Medical Sciences
Study Sponsor  ICMJE Sanjay Gandhi Postgraduate Institute of Medical Sciences
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Vikas Agarwal, MD, DM Sanjay Gandhi Postgraduate Institute of Medical Sciences
PRS Account Sanjay Gandhi Postgraduate Institute of Medical Sciences
Verification Date March 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP