NIH/NINR - End-of-Life and Palliative Care Approaches to Advanced Signs and Symptoms (R01, R21 Clinical Trial Optional)

The following was taken from the R01 version of this FOA:

While a fundamental goal of palliative care is to provide expert management of highly prevalent advanced symptoms in late stages of disease, on-going challenges in the alleviation of pain and other advanced symptoms remain — often with persistent levels of under-treatment. Advanced symptoms are problematic in many serious illnesses, including advanced cancer, advanced cardiovascular disease and heart failure, advanced respiratory illnesses, advanced renal and hepatic diseases, advanced neurological conditions, etc. Different than a broad approach to symptom management, a palliative focus on signs and symptoms occurs within the specific context of an advanced stage of a disease that must be treated amidst compounding conditions and unique EOL needs and challenges. For example, the management of advanced symptoms often occurs concurrently with life-extending disease management (e.g., chemotherapy, dialysis) or at end-stages of a condition, necessitating that care occurs within the framework of goal-directed, individual health care preferences and values. As death approaches, symptoms increase in number, intensify in severity (e.g., poor appetite, dyspnea, and fatigue) and result in a higher symptom burden, longer and more frequent hospitalizations and increased mortality. Usual treatments may become less effective, related to poor circulation, because of decreased tissue perfusion, or because of interactions with treatment for other symptoms the individual is experiencing. Impaired organ function may lead to magnified side effects because of the diminished ability of the hepatic and renal systems to filter medications. Advanced signs and symptoms (e.g., myoclonic jerking, constipation, nausea/vomiting) may also emerge secondary to opioid use. Terminal restlessness may result from pain, urinary retention or fecal impaction or may be the result of medications designed to treat other symptoms. These secondary effects need to be distinguished by detailed screening and assessments. Further, advanced disease states may represent multiple and progressive conditions. For example, hyponatremia occurs in approximately one-third of palliative patients and can result in layers of symptoms that are compounded by the primary disease state such as: breathlessness, depressive symptoms, nausea, vomiting, poor appetite, constipation, and weakness.

Despite the frequency, complexity and intensity of symptoms experienced by individuals at the end of life, research on advanced palliative symptom management remains insufficient to predict the precise therapies likely to provide adequate relief in specific individuals. Interventions are needed that

improve the experience of advanced symptoms in serious, advanced illness and may improve individual’s quality of life, optimize their use of appropriate pharmacologic and non-pharmacologic interventions, improve their ability to focus on what is important and reduce caregiver burden.

The state of the science regarding advanced signs and symptoms is highly variable. For some symptoms, diagnoses, and populations there is evidence of the foundations and experiences of certain advanced signs and symptoms and the need is for interventions that optimize palliative management strategies. Other areas need more exploratory research to describe the mechanisms and manifestations of advanced signs and symptoms. Advancing the science of palliative care requires careful assessment of the state of the evidence regarding a particular advanced sign or symptom and population. A strong scientific premise is needed to support the appropriate state of the science for proposed studies to address this complex field.

In the last stages of advanced illness, there are numerous and unique physical, emotional and social changes that affect how late-stage signs and symptoms are experienced and managed. These changes are not limited to the last days of life but may occur over months of a life-limiting condition in ways that have an unpredictable trajectory and uncertain prognosis. In addition to these specific challenges related to the advanced stage of illness, advanced signs and symptoms may be affected by a host of variables including age, medical complexities, genomic differences, environment, social and psychological factors. Issues such as sex as a biological variable, bioethics related to symptoms at the end of life, and social determinants of health may affect the experience and management of advanced signs and symptoms in serious illness. Hence, the complexity of the symptom experience, especially in people in the last phase of life, warrants broader conceptualization of advanced symptoms than has been characteristic in previous research.

There are numerous barriers to management of advanced symptoms at the end of life, including: individual/caregiver fears and concerns about pain medications and side effects, reluctance or inability to report symptoms, or a full understanding of the complexity of the advanced symptom experience. Some providers lack knowledge about how to disentangle assessment of compounded multi-morbidities, and which therapeutic approaches will overcome numerous secondary effects of therapies. There remains insufficient characterization of complex and often co-occurring advanced symptom phenotypes, knowledge of longitudinal changes, understanding of the mechanisms underpinning advanced symptoms, and variable responses to treatment outcomes. To build the evidence about palliative and end-of-life approaches to advanced signs and symptoms, investigators will need to address the barriers related to exploring this complex, multidimensional issue.

Research Objectives

NINR is interested in studies examining the multi-dimensional foundations, experiences and management of advanced signs and symptoms specific to individuals with advanced serious illness within the period of end of life (prognosis of 12 months or less) including, but not limited to:

Pain
Fatigue
Respiratory signs and symptoms, including dyspnea, audible secretions/congestion, cough, respirations with mandibular movement, hemoptysis, etc.
Cardiovascular signs and symptoms, including edema, cyanosis, weakness, etc.
Gastrointestinal or digestive signs symptoms, including anorexia, cachexia, constipation, diarrhea, dysphagia, involuntary bowel movements, nausea, stomatitis, vomiting, etc.
Urinary signs and symptoms including incontinence, urinary obstruction, decreased urinary output, etc.
Integumentary symptoms including itching, skin failure, etc.
Symptoms related to fluid balance including dizziness, dehydration, dry mouth, fever, etc.
Neurological and behavioral signs and symptoms including agitation, confusion, delirium, hallucination, irritability, myoclonus, seizures, sleep disturbances, terminal restlessness, etc.
Psychosocial signs and symptoms of anxiety, depression, loneliness, social withdrawal, social isolation, etc.
Signs associated with dying including cyanosis of extremities, cold extremities, mottling, etc.

It is strongly recommended that investigators communicate with the Scientific/Research Contact for this funding opportunity announcement prior to application.

Applications supported under this FOA will include those focused on:

Individuals with serious, advanced illness and limited prognosis (12 months or less)
Individual patient- and family-centered outcomes

Research projects may include descriptive and/or experimental studies that will lead to future mechanistic and intervention research.

Research projects of interest include, but are not limited to those that:

Explore and identify the mechanisms of complex advanced signs and symptoms at the end-of-life that may be modified to improve the symptom experience of the individual or family.
Explore the complex variables affecting the symptom experience including physiological, social, cultural and emotional variables and confounding variables such as other symptoms and underlying disease.
Describe how type, intensity, complexity and changes in trajectory of advanced symptoms impact individual and family goals for care.
Identify changes in the complex advanced symptom experience as serious illness progresses.
Describe the impact of advanced signs and symptoms on the seriously ill person and/or the family caregiver.
Explore and describe the roles of the ill person and the family caregiver in identifying, assessing and communicating with clinicians about advanced signs and symptoms.
Discover the best, minimally invasive methods to monitor individual- and family-reported outcomes such as symptom severity, symptom distress, and functional status related to advanced symptoms.
Develop, test and evaluate preventive interventions, for example, to address audible secretions/chest congestion, a description of the patient experience and the development, testing and evaluation of preventive measures such as oral hygiene.
Develop, test and evaluate efficient, effective strategies for management of complex, advanced signs and symptoms at the end-of-life, including non-pharmacological interventions and current medications. Symptoms of interest are listed above.
Develop, test and evaluate systems and models of care to implement personalized advanced palliative symptom management plans based on underlying mechanisms.

Research using animal models is not appropriate for this funding opportunity announcement.

Because of the complex, multi-factorial nature of this issue, multi-disciplinary teams are highly encouraged. Investigators are encouraged to consider using existing palliative care research networks, such as the Palliative Care Research Cooperative Group, to carry out small, multi-site trials when appropriate. Inclusion of patient- and family-representatives in the design of the study and in the development of interventions is strongly recommended. Inclusion of under-studied populations including NIH-designated health disparity, socioeconomically disadvantaged, rural and/or remote, and sexual and gender minority populations with advanced, serious illness at the end of life is encouraged. To fully explore the individual- and family-centered experience of advanced signs and symptoms, a wide variety of research methodologies may be appropriate including qualitative, mixed methods, quasi-experimental, laboratory, pragmatic techniques and innovative methods including visualization techniques.

Deadlines: standard dates and standard AIDS dates apply

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Filed Under: Funding Opportunities

NIH/NINR – End-of-Life and Palliative Care Approaches to Advanced Signs and Symptoms (R01, R21 Clinical Trial Optional)