Optimizing Patient-Reported and Vascular Outcome Measures in Systemic Sclerosis-Associated Raynaud Phenomenon
Abstract
Systemic sclerosis, also known as scleroderma, is a multisystem autoimmune disease that affects an estimated 80,000 Americans. Although uncommon, it has historically had the highest mortality rate of the rheumatic diseases. Raynaud phenomenon (RP) is the most common symptom of scleroderma, affecting > 95% of patients. RP is an episodic phenomenon where the blood vessels in the digits narrow in response to cold and/or emotional stress. In scleroderma patients, this can progress to complications such as digital ulcers. RP is often the first symptom of the disease and is ranked by scleroderma patients as the highest disease-specific symptom affecting their quality of life. Unfortunately, there are no U.S. Food and Drug Administration-approved therapies for the management of RP. This is disappointing, as there has been compelling rationale for the use of many of the previously tested drugs that did not show benefit in clinical trials. It has been observed that there are large placebo drug effects, or significant improvement in symptoms in those receiving the placebo. We have identified four knowledge gaps that are likely contributing to the placebo effect and hampering clinical trial design, so that we cannot detect effective therapies for RP. The primary goal of this proposal is to overcome these four critical knowledge gaps, and thus enable the research community to design better clinical trials in scleroderma-RP so that drugs may be approved for use in the future. Knowledge Gap 1: What is the best way to measure RP attack frequency and severity? Traditionally, self-report paper daily diaries have been used to obtain the frequency and duration of RP attacks over 2 weeks. This is felt to be burdensome by patients and is subject to multiple biases, such as behavior modification. We propose that a new smartphone application with specific features to ameliorate biases will be a better outcome measure. Knowledge Gap 2: What should we be using as the patient-reported outcome (PRO)? Trials have used an expert-designed question as the PRO to date. With patient focus groups and participation, we have been designing a new PRO. This proposal completes the development and validation of the new PRO (named the RAPIDS questionnaire) and tests its function against the older PRO. Knowledge Gap 3: Does seasonal change affect RP severity? RP is a cold-induced phenomenon, and thus variability in symptoms is likely affected by seasonal temperatures. How much this occurs is unknown. This proposal follows patients over 1 year to assess the magnitude of this change. This will help us learn the best length and enrollment period of trials. Knowledge Gap 4: What is the best way to measure skin blood vessel flow and function when testing drug for RP? Vascular reactivity has been tested in most trials by using cold-challenge in order to mimic RP. This involves cooling the patient’s hand. However, new knowledge about what underlies RP suggests that the damaging and severe aspects of scleroderma-RP may be related to blood vessel dysfunction. Thus, testing that give information on blood vessel function may be a better test. This proposal compares the cold-challenge test to the blood vessel function test. It also assesses how these tests may relate to the PRO instruments and frequency/duration of events. We plan to reduce the above-mentioned four knowledge gaps by performing an observational study where we evaluate 160 patients every 3 months over 1 year. We will ask patients to report their frequency/duration, fill out questionnaires, and undergo the vascular tests every 3 months. Their preference and test function will be analyzed to make recommendations on clinical trial outcome measures and design. An additional group of 340 patients will be recruited to help refine and validate the new RAPIDS questionnaire.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810602
Entities
People
- Robyn Domsic
Organizations
- United States Army
- University of Pittsburgh