FEATURE STORIES
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FEASIBILITY OF A NEW MODEL FOR EXERCISE
PRESCRIPTION IN CYSTIC FIBROSIS
FDA APPROVES PHASE 2 TRIAL OF POTENTIAL
IPF THERAPY GKT831
In a REACT Center pilot study, UAB pulmonologist Stefanie
Krick, MD, and physical therapist John Lowman, PT, PhD, will
examine the feasibility of a new, comprehensive exercise and
behavior intervention for patients suffering from cystic fibrosis
(CF).
Pulmonary exacerbations are the main cause for progressive
lung function decline, hospitalization, and mortality in patients
with CF. Current studies on the role of exercise in CF show
that physical exercise training has a positive effect on aerobic
exercise capacity, pulmonary function, and health-related
quality of life. However, almost all of these studies were
conducted in outpatient settings and were focused on short-
term outcomes.
The overarching hypothesis of this study is that providing both a
comprehensive exercise program and a behavioral intervention
during a two-week hospitalization for a pulmonary exacerbation
will be a long-term solution that enhances adherence to an
exercise program – and that adherence to this program will
result in improved, patient-centered outcomes.
The proposed study will enroll 20 hospitalized patients
admitted to UAB Hospital for an acute pulmonary exacerbation,
with a planned admission of 10-14 days, who do not have a
structured exercise regimen. Standard care includes antibiotic
and airway clearance therapies for 10-14 days. Participants also
will receive an exercise program and a behavioral intervention
that includes a heart rate/activity monitor, exercise log, and
exercise training manual. Clinical outcomes will be assessed at
admission and discharge and again at 2 weeks and 16 weeks
after discharge.
The comprehensive exercise program will include aerobic
and resistance exercise as well as addressing any individual
musculoskeletal/postural impairments. The exercise
intervention will be 30 minutes a day, 6 days a week, at
moderate intensity, alternating aerobic and resistance exercise.
The behavioral intervention, based on social-cognitive theory,
will include one-on-one coaching. In addition to the “in-
hospital intervention” period, participants will return to the UAB
Outpatient CF Clinic and receive a “booster” intervention 2-4
weeks after discharge, at which point the program is reviewed.
Results from this study will inform clinicians about the potential
costs, barriers, development needs, and scientific promise of
this proposed practice. If the planned intervention is found
to be effective in larger trials, then this model also could be
applied to other chronic medical conditions for which acute
exacerbations requiring hospitalization are common.
Victor Thannickal, MD
The U.S. Food and Drug
Administration (FDA) has approved
the start of a phase 2 clinical trial
of treatment candidate GKT831 for
idiopathic pulmonary fibrosis (IPF).
GKT831 is an orally available inhibitor
of the NOX1 and NOX4 enzymes.
NOX enzymes are known to help
generate reactive oxygen species
(ROS), high levels of which have
been associated with tissue damage.
In July 2018, the National Institutes of Health awarded an $8.9
million grant to Victor Thannickal, MD, director of the UAB
Division of Pulmonary, Allergy, and Critical Care Medicine, to
fund a multi-year research program focusing on the effect of
NOX enzymes in IPF. Dr. Thannickal’s research will assess the
safety and effectiveness of GKT831 in 60 patients on standard
of care treatment, comparing the potential therapy to placebo.
Participants will receive 400 mg of GKT831 twice a day, a dose
that showed anti-fibrotic and anti-inflammatory activity and had
an excellent safety profile in a phase 2 trial (NCT03226067)
in patients with the liver disease primary biliary cholangitis,
according to GKT831 maker Genkyotex.
The primary goal of the 24-week trial will be to assess the
change in plasma levels of o,o’-dityrosine, which can be a
marker of pulmonary oxidative stress and often is increased
in patients with interstitial lung disease. Researchers also
will evaluate changes in exercise capacity and lung function
through the 6-minute walk distance test and forced vital
capacity assessment.
Preclinical studies conducted on mice by Dr. Thannickal and
his team identified NOX4 as a key driver of lung fibrosis, as it
triggered the differentiation of fibroblasts into myofibroblasts
and was involved in the production of extracellular matrix,
which accumulates in patients with IPF.
Researchers also demonstrated that levels of NOX4 are
increased in people with IPF and that suppressing NOX1/4 with
GKT831 had anti-fibrotic effects and extended the survival of
aged mice with lung fibrosis. In turn, several models of lung
disease identified NOX1 as a driver of vascular remodeling,
which was reduced after treatment with GKT831.
“This is an important step forward in translating seminal
preclinical discoveries to patients with fibrotic lung disease,” Dr.
Thannickal says. “NOX1/4 inhibition may have profound disease-
modifying effects on the fibrotic and vascular remodeling,
which drives disease progression in IPF. We believe GKT831 has
the potential to be an effective IPF treatment.”