PF-00489791 For The Treatment Of Raynaud's

Study Overview
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Brief Summary
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The investigators propose that once daily administration of PF-00489791, a phosphodiesterase inhibitor, will reduce vasospasm and improve symptoms and signs associated with Primary and Secondary Raynaud's Phenomenon.

Official Title
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A Phase 2a Randomized Double-blinded, Placebo And Active Controlled Two Cohort Two Doses Cross-over Multi-center Clinical Study To Assess Efficacy Of A Once Daily Administration Of A Phosphodiesterase 5 Inhibitor (Pf-00489791) For The Treatment Of Vasospasm In Primary And Secondary Raynaud's Phenomenon

Conditions
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Raynaud's Disease, Peripheral Vascular Disease

Intervention / Treatment
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* Drug: PF-00489791
* Drug: PF-00489791
* Drug: PF-00489791
* Drug: PF-00489791
* Drug: PF-00489791
* Drug: PF-00489791
* Drug: PF-00489791
* Drug: PF-00489791


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Active Raynaud's Phenomenon Stable disease and medication requirements over the previous two months For Secondary Raynaud's Phenomenon subjects, a diagnosis of scleroderma using the American College of Rheumatology criteria or by the presence of at least 3/5 features of CREST syndrome both sexes Exclusion Criteria: Uncontrolled hypertension, diabetes mellitus, angina, or using oral nitrates Smoking within 3 months or smoking cessation using nicotine products Subjects currently taking sildenafil, tadalafil or vardenafil Subjects with ulnar arterial occlusive disease as shown by a modified Allen test Pregnant or breast feeding or considering pregnancy in next 4 months Participation in trial for investigational drug within 30 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Secondary Raynaud 4 mg dose (period 1)<br> | Drug: PF-00489791<br>* Subjects with Secondary Raynaud's Phenomenon will receive PF-00489791 4 mg once a day for the first 4 week cross over period and then placebo once a day for the second 4 week cross over period<br>|
| Experimental: Secondary Raynaud 4 mg dose (period 2)<br> | Drug: PF-00489791<br>* Subjects with Secondary Raynaud's Phenomenon will receive placebo once a day for the first 4 week cross over period and then PF-00489791 4 mg once a day for the second 4 week cross over period<br>|
| Experimental: Secondary Raynaud 20 mg dose (period 1)<br> | Drug: PF-00489791<br>* Subjects with Secondary Raynaud's Phenomenon will receive PF-00489791 20 mg once a day for the first 4 week cross over period and then placebo once a day for the second 4 week cross over period<br>|
| Experimental: Secondary Raynaud 20 mg dose (period 2)<br> | Drug: PF-00489791<br>* Subjects with Secondary Raynaud's Phenomenon will receive placebo once a day for the first 4 week cross over period and then PF-00489791 20 mg once a day for the second 4 week cross over period<br>|
| Experimental: Primary Raynaud 4 mg dose (period 1)<br> | Drug: PF-00489791<br>* Subjects with Primary Raynaud's Phenomenon will receive PF-00489791 4 mg once a day for the first 4 week cross over period and then placebo once a day for the second 4 week cross over period<br>|
| Experimental: Primary Raynaud 4 mg dose (period 2)<br> | Drug: PF-00489791<br>* Subjects with Primary Raynaud's Phenomenon will receive placebo once a day for the first 4 week cross over period and then PF-00489791 4 mg once a day for the second 4 week cross over period<br>|
| Experimental: Primary Raynaud 20 mg dose (period 1)<br> | Drug: PF-00489791<br>* Subjects with Primary Raynaud's Phenomenon will receive PF-00489791 20 mg once a day for the first 4 week cross over period and then placebo once a day for the second 4 week cross over period<br>|
| Experimental: Primary Raynaud 20 mg dose (period 2)<br> | Drug: PF-00489791<br>* Subjects with Primary Raynaud's Phenomenon will receive placebo once a day for the first 4 week cross over period and then PF-00489791 20 mg once a day for the second 4 week cross over period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Raynaud's Condition Score (RCS) at Week 4 | The Raynaud's Condition score (RCS) is participant's rating of difficulty considering number of attacks, duration, amount of pain, numbness, or other symptoms caused in the fingers (including painful sores) due to the Raynaud's phenomenon every day and impact of Raynaud's alone on use of hands every day. An 11 point Likert scale is used to rate the difficulty caused by the condition each day with 0 = no difficulty and 10 = extreme difficulty. Participants were asked to select the number that best describes their difficulty, with higher score indicating worse condition. Average daily score was considered for participants completing more than 1 Raynaud's pain score scale on a day. Baseline value was calculated as mean of the scores over 7 days prior to treatment start. Week 4 value was calculated as mean of the scores over the 7-day period prior to Week 4. | Baseline, Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Number of Raynaud's Attacks at Week 1, 2, 3 and 4 | Change from baseline in the number of Raynaud's attacks at Week 1, Week 2, Week 3 and Week 4 was calculated from the number of attacks reported over the 7-day period prior to each week from the patient diary, respectively. | Baseline, Week 1, Week 2, Week 3, Week 4 | 
| Change From Baseline in Mean Duration of Raynaud's Attacks at Week 4 | Mean duration of Raynaud's attacks for a time period was calculated as sum of recorded durations of attacks in the time period divided by total number of attacks in the time period where duration was recorded. | Baseline, Week 4 | 
| Change From Baseline in the Mean Raynaud's Pain Score at Week 1, 2, 3 and 4 | Participants were asked to rate their worst Raynaud's pain in the past 24 hours using an 11 point Likert scale, with 0 = no Raynaud's pain and 10 = the worst possible pain. Highest (most severe) response was considered for participants responding at more than 1 point on the scale. Average daily score was considered for participants completing more than 1 Raynaud's pain score scale on a day. Baseline value was calculated as mean of the scores over 7 days prior to treatment start. Post-baseline value was calculated as mean of the scores over the 7-day period prior to the visit. | Baseline, Week 1, 2, 3, 4 | 
| Number of Participants With Decrease From Baseline in Digital Ulcers at Day 14 and 28: Secondary Raynaud's Phenomenon Cohort | Presence of ulcer was assessed at baseline. At post-baseline visits, each ulcer was measured and scored: 1= smaller or improved compared to previous visit, 2= same as previous visit, 3= bigger or worse than previous visit, and 4= new. If a new digital ulcer develops during the course of the study, the measurement and scoring were initiated on this additional ulcer. Healed ulcers were not counted into the number of ulcers. Participants with SRP in the per-protocol population with at least 1 digital ulcer present at any assessment were evaluable for this measure. Results are reported for participants with presence of ulcer at baseline and decrease from baseline in ulcers at post-baseline visits. | Baseline, Day 14, 28 | 
| Plasma Concentration of PF-00489791 and Its Metabolites | Only participants receiving PF-00489791 were to be analyzed for this outcome. Data have been calculated by setting plasma concentration values below the lower limit of quantification to 0. The lower limit of quantification is 0.0100 microgram per milliliter (mcg/mL). Data for plasma concentration of PF-00489791 metabolites was not analyzed, as it was not intended to be a secondary endpoint and was deemed optional. | Day 1, 15, 29 (Day 1, 15, 29 for first intervention period), 43, 57, 71 (Day 1, 15, 29 for second intervention period) | 
| Number of Participants With Laboratory Test Abnormalities | Criteria for laboratory tests abnormalities included: hemoglobin, hematocrit and red blood cells (less than [<] 0.8*lower limit of normal[LLN]); leukocytes (<0.6 LLN /greater than [>] 1.5*upper LN [ULN]; platelets (<0.5*LLN/>1.75*ULN); neutrophils, lymphocytes (<0.8* LLN/>1.2*ULN); eosinophils, basophils, monocytes (>1.2*ULN); bilirubin (>1.5*ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), Gamma GT, alkaline phosphatase (>3*ULN); BUN, creatinine (>1.3*ULN); glucose (<0.6 LLN/>1.5*ULN); uric acid (>1.2*ULN); sodium (<0.95*LLN/>1.05*ULN); potassium, calcium, chloride, bicarbonate (<0.9*LLN/>1.1*ULN); albumin, total protein (<0.8*LLN/>1.2*ULN); creatine kinase (>2.0*ULN); Urine Specific Gravity, Urine pH, urine blood, urine glucose, urine protein, urine ketones, urine leukocytes esterase (>=1 high-powered field). Total number of participants with any laboratory abnormalities was reported. | Screening up to 28 days after last study dose (up to 98 days) | 
| Number of Participants With Clinically Significant Changes in Vital Signs and Orthostatic Blood Pressure Measurements | Vital signs assessment included measurement of supine and standing pulse rate, systolic and diastolic blood pressures. Criteria for clinically significant vital signs and orthostatic blood pressure measurements were based on investigator's judgement. | Screening up to 28 days after last study dose (up to 98 days) | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Values | ECG assessment included measurement of PR, QRS, QT,corrected QT interval (QTc)values. Criteria for clinically significant ECG values were based on investigator's judgement. | Screening up to 28 days after last study dose (up to 98 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Raynaud's phenomenon, vasospasm, scleroderma, systemic sclerosis, CREST, phosphodiesterase inhibitor