The most well-described symptoms of a disease are not always those that have the greatest impact on people living with the disorder
Traditionally, outcome measures — the observations investigators make in a clinical trial to decide whether one treatment is better than another or better than a placebo — are determined by factors in a disease that are considered important by physicians and other professionals.
But in recent years, there has been increasing interest in finding out what matters most to people with the condition being studied.
In a December 2009 "guidance for industry" document, the U.S. Food and Drug Administration (FDA) strongly suggested that investigators proposing a clinical trial for an experimental drug include patient-reported outcome (PRO) measures in their study design.
With an eye to developing PRO measures and increasing professionals' understanding of disease effects, MDA began in 2008 to support neuromuscular clinician and researcher Chad Heatwole at the University of Rochester (N.Y.) to study the experiences of people with myotonic muscular dystrophy (MMD1, or DM1) and facioscapulohumeral muscular dystrophy (FSHD).
Heatwole and colleagues published the results of the MMD1-related patient impact study July 24, 2012, in Neurology. They published the results of the FSHD-related study online (as an accepted manuscript) July 23, 2012, in Muscle & Nerve, with Nicholas Johnson at the University of Rochester as first author.
Both studies revealed some surprises for the investigators and offer guidance for both research and care.
"Physicians typically describe diseases with objective diagnostic criteria in mind," said Sanjay Bidichandani, MDA's vice president of research, "but when we think of evaluating experimental therapies, it's important to consider which symptoms matter to the patients themselves.
"These studies are important because they measure the relatively subjective symptoms that patients consider important to them so that future therapies may be evaluated in a more patient-centric and meaningful manner."
The MMD1 study — called PRISM-1 for "patient-reported impact of symptoms in myotonic dystrophy type 1" — was conducted in two parts.
Phase 1 involved interviews with 20 people age 21 or older with adult-onset MMD1. (People with congenital- or juvenile-onset MMD1 were not included in this study.)
In the interviews, people were asked to identify the symptoms of MMD1 that have the greatest effect on their lives. Recurring similar comments were grouped to identify 221 important MMD1 symptoms, which the investigators then divided into 14 themes. All 20 people who were invited to participate in this phase did so.
In phase 2 of the study, questionnaires were sent to 530 adults with MMD1 who had enrolled in the National Registry of Myotonic Dystrophy & FSHD Patients and Family Members. This registry, which remains open, is housed at the University of Rochester Medical Center and is supported by the U.S. National Institutes of Health (NIH).
Two questionnaires were developed, and recipients were randomly assigned to receive one or the other.
They included each potential symptom of importance identified in the phase 1 interviews and asked responders to evaluate the impact of the symptom on his or her life on a scale of 1 to 6. A score of 1 indicated, "I don't experience this," and a score of 6 indicated, "It affects my life severely," with other scores indicating impact between these two extremes.
Of those who were sent questionnaires, 278 (52 percent) replied.
The symptom themes that were cited most often by survey responders were, in order:
However, the symptom themes that had the greatest impact on people's lives were identified as fatigue and limitations in mobility.
There was an association of older age with increased prevalence (existence) of symptoms. In addition, the size of the expanded CTG repeat section on chromosome 19 — the genetic defect that underlies MMD1 — correlated with the average impact of all symptom themes on participants' lives, with greater CTG repeat lengths accompanying greater impact of symptoms.
As in the MMD study, the FSHD study conducted 20 interviews with adults age 21 or older with FSHD. Participants were asked to identify which symptoms had the greatest impact on their quality of life and to describe how their lives were affected by having FSHD.
The investigators identified 251 important symptoms, representing 14 symptom themes.
This study did not include a survey phase, but the questionnaire for that is being developed, and a survey is being planned, said study author Nicholas Johnson.
The most often mentioned symptoms in the interviews, in order of frequency, were:
The three most common themes in the interviews, in order of frequency, were:
In the MMD1 study, the authors note that their research demonstrates that the most well-described manifestations of a disease are not always those that have the greatest impact on the lives of people with the disorder.
"The medical literature does not generally report fatigue as the primary symptom of DM1 [MMD1]," they say; "however, participants reported this symptom as having the greatest overall effect."
In the FSHD study, the authors note, "The effect FSHD has on a patient's social role and emotional status is often overlooked in the clinical setting, yet these issues have a paramount importance to patients, as highlighted through our interviews. Indeed, the frequency that patients mention the importance of social role limitations was greater than the frequency of quotes involving the cardinal features of FSHD (facioscapulohumeral weakness)."
Although not specifically addressed in the paper, it's also noteworthy that FSHD is often described as primarily involving facioscapulohumeral weakness — weakness of the muscles of the face, shoulder blade area and upper arm — but that people with the disease reported impaired walking ability as their most important concern.
A caveat to relying solely on patient-reported data, however, also was noted by the authors of the MMD1 study. They say some signs of cardiac or respiratory impairment in MMD1 may be below conscious awareness, despite their importance to health.
The National Registry of Myotonic Dystrophy & FSHD Patients and Family Members aims to advance research in MMD and FSHD by helping to recruit participants for clinical studies in these disorders.
The University of Rochester website for this registry says no identifiable information about registry members will be provided to anyone, and that if a registry member is eligible to participate in a study, the registry will contact the member and give him or her contact information for the researcher.
You can download the application materials from the registry, or you can call (888) 925-4302 or (585) 276-0004 in Rochester, N.Y.
Here's a list of the resources cited in this article: