Personalized Exercise Therapy and Self-management for Patients With Multimorbidity
Personalized Exercise Therapy and Self-management for Patients With Multimorbidity
Chronic conditions such as knee or hip osteoarthritis (OA), chronic obstructive pulmonary
 disease (COPD), heart failure (HF), coronary heart disease (CHD), hypertension, type 2
 diabetes mellitus (T2DM) and depression are among the leading causes of global disability and
 affect hundreds of millions of people around the world. In recent years, multimorbidity,
 commonly defined as the co-occurrence of at least two chronic conditions, has also gained
 interest due to its substantial impact on the person and society.

 Despite the significant burden of multimorbidity, little is known about how to treat this
 effectively. A 2016 Cochrane systematic review found that interventions targeting populations
 with specific combinations of conditions and addressing specific problems such as functional
 difficulties may be more effective. Exercise therapy is a treatment addressing functional
 limitations that is a safe and effective treatment of at least 26 chronic conditions,
 including OA, HF, CHD, hypertension, T2DM, COPD and depression. Furthermore, self-management
 is increasingly recognized as an essential component of interventions to improve outcomes in
 patients living with multimorbidity and to support the long-term adherence to exercise. A new
 systematic review found that exercise seems effective in people with multimorbidity (the
 conditions included in the current study), however highlighting the need for further
 high-quality RCTs.

 The aim of this randomized controlled trial (RCT) is to investigate the effects of a
 personalized exercise therapy and self-management program in addition to usual care on
 self-reported, objectively measured and physiological outcomes in people with multimorbidity
 (i.e. at least two of the following conditions: OA (knee or hip), heart condition (HF or
 CHD), hypertension, T2DM, COPD and depression). The primary endpoint is 12 weeks, but 6-month
 and 12-month follow-ups are included to investigate the medium and long term and health
 economic effects of the program.

 Prior to the RCT, a feasibility trial of 20 people with multimorbidity, all undergoing the
 personalized exercise therapy and self-management program, will be conducted using the same
 methods as in the RCT, but primarily focusing on feasibility outcomes (recruitment,
 retention, adherence to treatment, burden of outcomes, improvements in outcomes, adverse
 events). This will start recruitment in Feb 2021 and end August 2021.

 The MOBILIZE project has received funding from several foundations, including the European
 Research Council (ERC) under the European Union's Horizon 2020 research and innovation
 program (grant agreement No 801790).
Chronic conditions such as knee or hip osteoarthritis (OA), chronic obstructive pulmonary
 disease (COPD), heart failure (HF), coronary heart disease (CHD), hypertension, type 2
 diabetes mellitus (T2DM) and depression are among the leading causes of global disability and
 affect hundreds of millions of people around the world. In recent years, multimorbidity,
 commonly defined as the co-occurrence of at least two chronic conditions, has also gained
 interest due to its substantial impact on the person and society. In general, multimorbidity
 affects more than half of all people with chronic conditions. Two out of three people with OA
 have comorbidities, with HF, CHD, hypertension, T2DM, COPD and depression being some of the
 most common.

 People with multimorbidity account for 78% of all consultations in primary care and
 multimorbidity is associated with poorer function and quality of life, depression, intake of
 multiple drugs and increased health care utilization, with some studies demonstrating an
 almost exponential relationship between the number of chronic conditions and their health
 care costs. Furthermore, we know from qualitative research that treating one condition at a
 time is inconvenient, inefficient and unsatisfactory for the person with the chronic
 conditions and his or her health care provider. Most research so far has excluded people with
 multimorbidity, due to its focus on only one specific condition, and most of the health care
 sector manages each individual condition on its own instead of the person, highlighting the
 negative impact of the current disease-based curative models on multimorbidity. With a
 population that is ageing, and a significant number of people with multimorbidity being
 younger than 65 years of age, the proportion of people with multimorbidity is increasing
 rapidly, emphasizing the need to take action to deal with the increasing burden of chronic
 conditions and multimorbidity through treatment and prevention.

 Identifying and developing effective and affordable treatment strategies to deal with the
 global burden of chronic conditions and multimorbidity is a major focus of modern health care
 around the world. Despite the significant burden of multimorbidity, little is known about how
 to treat this effectively. A 2016 Cochrane systematic review found that interventions
 targeting populations with specific combinations of conditions and addressing specific
 problems such as functional difficulties may be more effective. A treatment addressing
 functional limitations that is able to improve symptoms in at least 26 chronic conditions,
 including OA, HF, CHD, hypertension, T2DM, COPD and depression is readily available. This
 treatment is exercise therapy, which is effective, safe and supported by substantial evidence
 in patients with knee and hip OA, HF and CHD, hypertension, T2DM, COPD, depression and a
 range of other chronic conditions. A new systematic review found that exercise seems
 effective in people with multimorbidity (the conditions included in the current study),
 however highlighting the need for further high-quality RCTs. Furthermore, self-management is
 increasingly recognized as an essential component of interventions to improve outcomes in
 patients living with multimorbidity. There is increasing evidence that effective management
 of multimorbidity requires the active participation by patients in the care process.
 Self-management interventions have been shown to change health behaviors, improve health
 status, and reduce health care utilization and costs. Self-management support is centered on
 enabling patients to develop a set of behavioral skills and abilities to help them navigate a
 range of disease management tasks across different chronic conditions.

 In an RCT of people with knee OA, published in the New England Journal of Medicine, we found
 that 3 out of 4 patients eligible for total knee replacement improved enough from
 self-management, supervised exercise therapy and other non-surgical treatments to postpone
 surgery for at least one year. Furthermore, in patients with T2DM, 56% did not take
 antidiabetic medication after 1 year of supervised exercise therapy, self-management and
 diet. Together, these studies indicate the potential of combining exercise, self-management
 and other treatments to reduce the need for surgery and medication. A recent cohort study
 found that an eight-week exercise and self-management program demonstrated similar
 improvements in health outcomes for people with OA and the comorbidities included in the
 current study as for people without comorbidities.

 Altogether, this highlights exercise therapy and self-management as viable treatment options
 for people with multimorbidity, but the evidence supporting this is of low quality and more
 high-quality RCTs are needed to improve care for the millions of people suffering from
 multimorbidity worldwide.

 The overall aim of the MOBILIZE project is to empower patients with multimorbidity to take a
 more active role in their health care through a personalized exercise therapy and
 self-management program so that they may reduce symptoms of the individual conditions,
 increase quality of life and physical function and prevent development of other chronic
 conditions. To ensure relevance to the patients and the health care system and to make sure
 that the project is implementable in clinical practice afterwards, strong interdisciplinary
 collaboration involving many different scientific methodologies and a high degree of patient
 involvement throughout the entire research process are at the heart of the project. The
 MOBILIZE project has received funding from several foundations, including the European
 Research Council (ERC) under the European Union's Horizon 2020 research and innovation
 program (grant agreement No 801790). Building on the Medical Research Council's framework for
 the development and evaluation of complex interventions, the MOBILIZE project has four
 phases. During the first phase of the project, outcomes and biomarkers that predict better
 health outcome from different types of exercise therapy and exercise characteristics
 associated with a better outcome in people with different combinations of chronic conditions
 will be identified through exploratory observational cohort studies of people with
 osteoarthritis who have undergone an 8-week exercise therapy and education program in Denmark
 (GLA:D) as well as scoping reviews, systematic reviews and meta-analyses that summarize the
 existing evidence. Subsequently, in phase 2, a 12-week exercise therapy and self-management
 program will be developed based on existing recommendations for exercise and strategies to
 facilitate behavioral changes. To ensure a high degree of patient and provider involvement,
 focus group interviews will be conducted with patients with multimorbidity, health care
 providers and other relevant stakeholders to acquire their views and perspectives on
 multimorbidity and exercise. Once this phase is completed, the exercise therapy and
 self-management program will be tested in a feasibility trial involving 20 patients with
 multimorbidity (recruited from Feb 2021 and onwards). The same procedures and outcomes as in
 the subsequent RCT will be used, and data will be collected at baseline and immediately after
 the intervention (12 weeks). The feasibility trial will primarily focus on feasibility
 outcomes (recruitment, retention, adherence to treatment, burden of outcomes, improvements in
 outcomes, adverse events), using a red/amber/green traffic light system, guiding the
 progression to the subsequent RCT. Experiences from the feasibility trial will be used to
 evaluate and implement any adjustments that need to be made prior to commencing the RCT
 (described in details in the current trial registration). The RCT corresponds to phase 3,
 while phase 4 focuses on developing a model for implementation of the personalized exercise
 therapy and self-management program in clinical practice, if supported by the study findings.

 The aim of the RCT described in this clinical trial registration is to investigate the
 effects of a personalized exercise therapy and self-management program in addition to usual
 care on self-reported, objectively measured and physiological outcomes in people with
 multimorbidity (i.e. at least two of the following conditions: OA (knee or hip), heart
 condition (HF or CHD), hypertension, T2DM, COPD and depression). The primary endpoint is 12
 weeks, but 6-month and 12-month follow-ups are included to investigate the medium and long
 term and health economic effects of the program.

 The primary study hypothesis is that a personalized exercise therapy and self-management
 program in addition to usual care will improve quality of life and physical function more
 than usual care alone, when measured immediately after the program (12 weeks) with concurrent
 positive effects on secondary outcomes. Furthermore, it is hypothesized that improvements
 immediately after the program (12 weeks) will be sustained in the medium and long term (6 and
 12 months) and that the program will be cost-effective.

 People who only fulfill some of the eligibility criteria (at least 18 years old, at least two
 of the relevant conditions and do not have an unstable health condition or are at risk of
 serious adverse events as evaluated by a medical specialist and do not have psychosis
 disorders, post-traumatic stress disorder, Obsessive Compulsive Disorder, attention deficit
 hyperactivity disorder, autism, anorexia nervosa/bulimia nervosa or an abuse) and people
 fulfilling all eligibility criteria, but are unwilling to participate in the RCT, will be
 offered participation in an observational cohort study where only the self-reported outcomes
 are completed. Recruitment for the cohort will start and end with the recruitment for the
 RCT.
Inclusion Criteria:

 -  At least two of the following conditions: OA (knee or hip), COPD, heart condition (HF
 or CHD), hypertension, T2DM, depression (having other comorbidities does not exclude a
 patient)

 -  Adults aged 18 years or above

 -  Able to walk 3 meters without any assistance

 -  A score of 3 or above on the Bayliss' Disease Burden: Morbidity Assessment by Self-
 Report scale

 -  Willingness and ability to participate in a 12-week supervised exercise therapy and
 self- management program twice a week

 Exclusion Criteria:

 -  Participation in supervised systematic exercise for one of their diseases within the
 last 3 months

 -  Patients with an unstable health condition or at risk of serious adverse events as
 evaluated by a medical specialist

 -  Patients categorized as Class IV on the New York Heart Association (NYHA) Functional
 Classification scale

 -  Terminal patients and patients with life expectancy of less than 12 months

 -  Patients with psychosis disorders, post-traumatic stress disorder, Obsessive
 Compulsive Disorder, attention deficit hyperactivity disorder, autism, anorexia
 nervosa/bulimia nervosa and patients with an abuse

 -  Other reasons (unable to understand Danish, mentally unable to participate, etc.)