Clinical trial NCT03469271
Conditions: Cancer
Keywords: Pneumonia
Sponsor: Mayo Clinic
Start date: 2018-05-25; Completion date: 2020-05-21
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
This research is intended to begin to explore the impact of inspiratory muscle resistance exercise and/or 1,25(OH)2D3 for improving respiratory muscle strength in cancer patients (subjects).

Detailed description:

Arms: arm 1: Inspiratory isometric resistance training with the Threshold Inspiratory Muscle Trainer (IMT) plus oral placebo for eight weeks arm 2: Sham inspiratory isometric resistance training with the Threshold Inspiratory Muscle Trainer (IMT) plus 1,25 (OH)2 D3 orally for eight weeks arm 3: Inspiratory isometric resistance training with the Threshold Inspiratory Muscle Trainer (IMT) plus 1,25(OH)2 D3 orally for eight weeks arm 4: Sham inspiratory isometric resistance training with the Threshold Inspiratory Muscle Trainer (IMT) plus oral placebo orally for eight weeks
Interventions: intervention 1: 1,25 (OH)2 D3 intervention 2: Inspiratory isometric resistance training intervention 3: Oral Placebo intervention 4: Sham Inspiratory Isometric Resistance Training intervention 5: Threshold Inspiratory Muscle Trainer (IMT)
Intervention descriptions: intervention 1: 0.25 micrograms, taken daily for eight weeks, orally intervention 2: A small hand-held reusable device to increase muscle strength and endurance through inhalation therapy. Participants will inhale through a valve which provides resistance that increases the work of breathing and exercises the respiratory muscles.Participants in the active groups will breathe against a resistance set to generate 30% of maximal inspiratory pressure (PImax). intervention 3: Placebo will be created to mimic the appearance of the study drug intervention 4: A small hand-held reusable device to increase muscle strength and endurance through inhalation therapy. Participants will inhale through a valve which provides resistance that increases the work of breathing and exercises the respiratory muscles. Participants in the sham group will train daily against a resistance set to only 15% PImax. intervention 5: A small hand-held reusable device to increase muscle strength and endurance through inhalation therapy. Participants will inhale through a valve which provides resistance that increases the work of breathing and exercises the respiratory muscles.

Protocol documents:
Prot_SAP_000.pdf: 
Version v.2 09.07.2018 
 
 
 
 
 
 
 
 
 
 
 
 
ID: 17-009440 Resistance Training and 1,25(OH)2D3 Administration to 
Maintain Respiratory Muscle Function and Reduce Pneumonia Risk in 
Cancer Patients 
 
 
 
 
 
 
ClinicalTrials.gov ID NCT03469271 
 
 
 
Document Date 1/08/18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version v.2 09.07.2018 
 
2
 
 
 
 
 
 
 
 
 
Resistance Training and 1,25(OH)2D3  Administration to Maintain 
Respiratory Muscle Function and Reduce Pneumonia Risk in Cancer 
Patients 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATORS: Aminah Jatoi, M.D. and Gary Sieck, Ph.D. 
 
Co-Investigator:  Rajiv Kumar, M.D. 
 
 
 
 
Funding Sponsor:  Andersen Foundation 
 
 
 
 
 
IRB 17-009440  
 
 
 
Version: v.2 January 8, 2018 
 
 
 
 
 
 
 
 
 
 
 
 


Version v.2 09.07.2018 
 
3
 
1.0 INTRODUCTION 
 
Pneumonia as a Problem in Older Cancer Patients. Pneumonia is a major cause of mortality in 
both older patients and cancer patients. Rates of pneumonia triple among individuals who are 
65 years of age and older, and billions of dollars go toward the treatment of this life-threatening 
complication. Although less research along these lines has been conducted in cancer patients, 
>30% of patients with cancer develop pneumonia, resulting in death under some circumstances; 
and, importantly, our group's published preliminary data, which show under-reporting of causes 
of morbidity and mortality in cancer patients, suggest this percentage is a gross 
underestimation.  The fact that cancer is now a disease of older patients only heightens 
concerns for this increased risk of respiratory morbidity and mortality and only further 
underscores the need to intervene to reduce this risk.  This proposal recognizes this double 
threat – older age and cancer – acknowledges that pneumonia is a major source of morbidity 
and mortality in older cancer patients, and, ultimately, aims to reduce this risk.  
  
Importantly, work from the Sieck laboratory shows that weakness of the diaphragm muscle 
(the major inspiratory muscle) due to wasting of more fatigable fast-twitch muscle fibers 
results in compromised coughing and sneezing.  These circumstances impair an individual’s 
ability to clear his/her airway and place that person at greater risk for pneumonia.  Such 
selective wasting and weakening of diaphragm muscle fibers can occur in a variety of 
conditions, but recently the Sieck laboratory showed that it also occurs with aging. In addition, 
multiple studies demonstrate that generalized muscle wasting occurs in over 80% of 
patients with advanced cancer and that this commonly observed clinical phenomenon is 
tightly associated with shortened survival.  We contend that muscle wasting from aging and 
muscle wasting from cancer represent a double threat for older cancer patients and that 
mitigating the atrophy and weakening of diaphragm muscle fibers is a prime therapeutic target 
that will lead to a reduction in respiratory morbidity and mortality and thereby improve survival in 
older cancer patients. 
 
Interventions that May Prevent Morbidity.  Interestingly, data from our group and others suggest 
that, in the setting of cancer, two interventions appear to improve the strength of respiratory 
muscles and prevent this complication of pneumonia: inspiratory muscle resistance (strength) 
training and the administration of the vitamin D metabolite, 1,25-dihydroxyvitamin D3 
(1,25(OH)2D3).  First, over the years, inspiratory muscle resistance (strength) training to treat 
chronic obstructive pulmonary disease, obstructive sleep apnea, neuromuscular diseases, and 
other diseases has shown increasing promise. Second, our group observed that 1,25(OH)2D3  
exposure results in an increase in mitochondrial oxygen consumption rate and increased protein 
synthesis in human skeletal muscle cells; these changes that suggest 1,25(OH)2D3  
administration could ultimately lead to improved respiratory muscle strength and less respiratory 
morbidity and mortality in older cancer patients.  
  
Hypothesis.  This proposal is unique because: 1) the impact of inspiratory muscle resistance 
exercise for improving respiratory muscle strength in older cancer patients has not yet been  
investigated in a clinical setting and, 2) to our knowledge, no studies have tested the  
administration of 1,25(OH)2D3  among older cancer patients  -- or in cancer patients in general  --   
to maintain inspiratory muscle strength and to reduce respiratory morbidity.   
 
The central hypothesis of this proposal is that inspiratory muscle resistance exercise 
and the  
administration of 1,25(OH)2D3 result in an increase in inspiratory muscle strength in older  
cancer patients.    
 


Version v.2 09.07.2018 
 
4
 
 
 
 
2.0 BACKGROUND: 
 
Muscle Loss in Older Cancer Patients.  Over 80% of patients with incurable cancer suffer 
weight loss [1]. This weight loss is derived largely from loss of lean tissue and is associated with 
early death and debility [2,3,4]. Emphasizing the vital role of lean tissue, Roubenoff and 
Kehayias provide evidence that loss of 45% or more lean tissue is incompatible with life [5]. 
Weight loss has been cited as the sole cause of death at autopsy in as many as 20% of cancer 
patients [1]. In a 1400-patient study, Martin and others observed that 53% of cancer patients 
had lost muscle, as determined by CT scan measurements at the L3 vertebral level, and that 
this muscle loss is an independent predictor of poor survival (p< 0.001) [4].  Because this same 
loss of muscle occurs as a direct result of aging – termed “sarcopenia” -- the development of 
cancer in an older individual creates, in effect, a double threat that places older cancer patients 
at greater risk for all the morbidity described above [5].  Finally, despite the testing of multiple 
interventions, to date, no intervention has been shown to augment lean tissue and improve 
survival. 
 
What Do These Weight-/Muscle-Losing Cancer Patients Die From?  To date, early death in 
older, weight-losing cancer patients has been clearly demonstrated but poorly characterized.  
What do weight-/muscle-losing cancer patients die from?   An estimated 30% are diagnosed 
with pneumonia, a cause of death that could be linked to muscle wasting [8-13]; however, 
our previously published work suggests this percentage is a gross underestimate [14].   
 
Importantly, the Sieck laboratory has shown that age-related muscle loss leads to compromised 
coughing and sneezing and an inability to clear the airway [15-18].  The current proposal is 
unique in that it brings work from the Sieck laboratory into the clinic for the first time, 
begins to examine this work within the context of cancer, and further expounds upon – 
and proposes to break – these ostensible links between muscle wasting, incidence of 
pneumonia, and early death in older cancer patients. 
 
The Benefits of Exercise, Logistics, and Measuring Outcomes.  For decades, inspiratory 
muscle resistance (strength) training has been tested in chronic obstructive pulmonary disease, 
obstructive sleep apnea, neuromuscular diseases, and other diseases with emerging success 
[19-24]. In cancer-associated weight loss, a meta-analysis described inconclusive findings [25], 
but, in multiple other cancer settings – including, for example, cancer-induced fatigue and 
cardiovascular morbidity in cancer survivors – exercise in general appears to improve clinical 
outcomes [26-29]. For inspiratory muscle strength, portable devices enable patients to 
participate in resistance exercise programs at home 
(https://www.usa.philips.com/healthcare/product/HCHS730010/treshold-inspiratory-muscle-
trainer); we propose to use one of these devices here to begin to test the hypothesis that the 
use of such devices can improve diaphragmatic strength and reduce pneumonia risk in 
older cancer patients.   
 
Respiratory muscle strength will be assessed by measuring the maximal inspiratory muscle 
strength (MIP or PImax) and maximal expiratory pressure (MEP or PEmax). In addition the 
SNIP test (sniff nasal inspiratory pressure) will also be performed by subjects to measure 
inspiratory muscle strength. It is particularly important in measuring muscle force exerting from 
the diaphragm. This test requires only that patients “sniff” forcefully through one nostril. .  The 
best and worst of 10 measurements are recorded.  


Version v.2 09.07.2018 
 
5
 
1,25(OH)2D3 and Its Potential Role in Treating Muscle Wasting. In preclinical data, our group 
has shown that 1,25(OH)2D3 appear to mitigate cancer-associated muscle wasting.  Exposure of 
human skeletal muscle cells to Lewis lung carcinoma cells led to changes in mitochondrial 
fusion/fission mediator proteins, mitochondrial fragmentation, and mitochondrial oxygen 
consumption rate  -- all of which are consistent with and conducive to muscle fiber atrophy.  
However and importantly, the additional exposure of these cells to 1,25(OH)2D3 abrogated these 
changes.  Such preclinical findings give rise to the hypothesis that the administration of 
1,25(OH)2D3 will reverse muscle wasting and its associated morbidity, including the 
development of pneumonia, and will thereby decrease the morbidity and mortality of cancer-
associated muscle wasting.  In conjunction with exercise, as alluded to above, the possibility of 
reducing pneumonia risk and improving survival may be even greater. The above hypothesis 
becomes all the more interesting and imminently testable in view of the fact that a safe and 
often clinically used dose of 1,25(OH)2D3 has already been determined.  A dose of 0.25 
micrograms per day is often prescribed safely to patients with renal osteodystrophy and, 
therefore, appears to be a reasonable dose to test in this proposal. 
 
3.0 STUDY OBJECTIVES 
 
3.1  To explore the effect of inspiratory muscle resistance training on inspiratory muscle 
strength. 
3.2  To explore the effect of 1,25(OH)2D3 administration on inspiratory muscle strength. 
3.3  To explore the combined effect of inspiratory muscle resistance training and 1,25(OH)2D3 
administration on inspiratory muscle strength.  
 
In short, this work is intended to provide point estimates and standard deviations for the effects 
of an 8-week interventions on the “sniff test” as described in the 4-arm study below. 
 
 
4.0 STUDY DESIGN 
 
This is a randomized, double-blinded dummy pilot study design (n=60 with 15 patients to be 
assigned to each study arm):   
 
 


Version v.2 09.07.2018 
 
6
 
 
 
PRIMARY STUDY ENDPOINT: To acquire descriptive data on the SNIFF after 8 weeks 
of the above interventions.   
 
SECONDARY STUDY ENDPOINT:  To acquire data on the safety of inspiratory 
isometric resistance and 1,25(OH)2D3 
 
 
5.0  IDENTIFICATION OF SOURCE DATA 
 
The following source data will be directly recorded on case report forms: 
• 
Vital signs at baseline and at 8 weeks 
• 
Bilirubin, creatinine, serum calcium and phosphorous at baseline 
• 
SNIP TEST results at baseline, 2, 4 and 8 weeks  
• 
MIP and MEP TEST results at baseline, 2, 4 and 8 weeks 
• 
Serum calcium and phosphorous levels at 2,4, and 8 weeks 
• 
Adverse events 
 
 
6.0  PATIENT ELIGIBILITY [30-32] 
 
Eligibility Criteria:  
 
1) 18 year of age or older 
 
2) diagnosis of cancer 
 
3) renal and hepatic function (creatinine </= 2 x the institutional upper limit of normal;  bilirubin 
</= 2 x the institutional upper limit of normal) 
 


Version v.2 09.07.2018 
 
7
4) no contraindication to receive either of the planned interventions of inspiratory resistance 
training or 1,25(OH)2D3 in the opinion of the healthcare provider  
 
5) no difficulties with swallowing oral medications in the opinion of the enrolling physician (no 
documentation necessary in the medical record).   
 
Contraindications:               
 
1) Patient is taking calcium or vitamin D supplements and is unwilling to stop for 8 weeks 
 
2) Severe chronic obstructive pulmonary disease (oxygen dependent or patient self-reports 
unable to walk one block without difficulty 
 
3) Calcium or phosphorous level above the institutional upper limit of normal 
 
Subject Recruitment: 
 
Patients will be recruited from all the clinical facilities at the Mayo Clinic in Rochester, 
Minnesota. The study team will rely on referrals from healthcare providers. 
 
 
Early Patient Withdrawal:  Patients can withdraw from the study at any time based on their 
wishes. In the event that an intervention-related adverse event occurs, patients will be 
withdrawn from the study by the study team. 
 
Patients who develop an increase in their calcium or phosphorous level above the institutional 
baseline will be taken off the study agent/placebo and referred to their primary healthcare 
provider. Patients will be given the option to continue on with the inspiratory resistance training 
to complete the eight week training period. 
 
Human Subjects  
  
1. Risks to the subjects 
 
Human Subjects Involvement and Characteristics:  All protocols and all techniques to be used 
will be approved by the Mayo Clinic Institutional Review Board prior to initiation of any studies. 
Subject characteristics and inclusion/exclusion criteria have been clearly specified above. Our 
plan is to complete the study on 60 participants with 15 in each group. We are anticipating a target 
accrual of 75 subjects to account for anticipated dropout. In order to have 60 participants complete 
the study.  
    
Sources of Materials: Samples of blood, obtained during the study will be used exclusively for 
research purposes. 
 
Potential Risks:  The following are the potential risks for this study: 
 
a) Blood will be withdrawn. The risks of drawing blood include, pain, bruising, 
lightheadedness, and/or fainting, or rarely, infection at the site of the needle stick.  
b) Blood Pressure will be measured. The cuff can cause discomfort when pumped up and 
becomes tight. This is temporary discomfort. 
c) Isometric resistance training. Participating in unaccustomed exercise may include the risk 
of chest wall soreness.  


Version v.2 09.07.2018 
 
8
d) 1,25 (OH)2D3 agent intervention. Although rare, potential risks include: weakness, 
headache, nausea, vomiting, sleepiness, dry mouth, constipation, muscle pain, bone pain, 
or a metallic taste. 
 
 
 
 
 
7.0  STUDY INTERVENTIONS 
 
1)  1,25(OH)2D3 .  As per Drug Bank., this agent is used to treat vitamin D deficiency or 
insufficiency, refractory rickets (vitamin D resistant rickets), familial hypophosphatemia and 
hypoparathyroidism, and in the management of hypocalcemia and renal osteodystrophy in 
patients with chronic renal failure undergoing dialysis. This protocol will use doses that are 
identical to those used for these other clinical indications.  
 
Also, as per Drug Bank, the first pathway involves 24-hydroxylase activity in the kidney; this 
enzyme is also present in many target tissues which possess the vitamin D receptor such as the 
intestine. The end product of this pathway is a side chain shortened metabolite, calcitroic acid. 
The second pathway involves the conversion of calcitriol via the stepwise hydroxylation of 
carbon-26 and carbon-23, and cyclization to yield ultimately 1a,25R(OH)2-26,23S-lactone D3. 
The lactone appears to be the major metabolite circulating in humans. Enterohepatic recycling 
and biliary excretion of calcitriol occur. The metabolites of calcitriol are excreted primarily in 
feces. Cumulative excretion of radioactivity on the sixth day following intravenous administration 
of radiolabeled calcitriol averaged 16% in urine and 49% in feces. 
 
Patient instructions:  Patients will be instructed to take 1 tablet/placebo once per day. 
 
2) Inspiratory isometric resistance exercise.  Patients will be provided with a power breath 
device and will be instructed on how to use it.  Inspiratory muscle resistance training involves 
subjects being exposed to 10-15 minutes of training per day each day for 8 weeks using a 
commercially available inspiratory threshold-training device. Subjects will be asked to gradually 
increase training to 20-30 minutes per day or two 15 minute sessions.  
(https://www.usa.philips.com/healthcare/product/HCHS730010/treshold-inspiratory-muscle-
trainer). The inspiratory muscle training groups will breathe against a resistance set to generate 
30% of PImax (as estimated by a “sniff” test). Patients in the sham group will train daily against a 
resistance set to only 15% PImax.   
 
Method for Assigning Subjects to Treatment Groups. 
Patients will be randomly assigned to one of the 4 treatment arms with stratification based on 
the following: 
 
1) sex:  male versus female  
 
2) patient-reported degree of weight loss in the preceding 3 months:  >/=5% versus < 5% (or no 
weight loss). 
 
3) patient reported history of pneumonia in the past five years: yes or no  
 
Preparation and Administration of Study Drug. 
 
The Mayo Clinic Pharmacy will generate 1,25(OH)2D3 tablets 0.25 micrograms along with 
identical placebo. Assignment will remain blinded to patients, healthcare providers, and 
members of the study team who have direct patient contact.  


Version v.2 09.07.2018 
 
9
 
A member of the study team who has no patient contract will set the resistance on the 
inspiratory; the resistance gauge will then be effaced with rubbing alcohol. 
 
 
 
 
 
Monitoring. 
 
 
 
*adherence questionnaire and arm assignment questionnaire (see Appendix 1) 
 
SAMPLE SIZE AND STATISTICS.  A total of 15 patients per arm (60 total) will be included in 
this study.  This sample size is based on precedent from other trials that were aimed at 
obtaining data on point estimates of efficacy and standard deviations.  All data, including patient 
demographics and adherence data, will be presented descriptively with means, medians, 
percentages, ranges, standard deviations, and 95% confidence intervals, as appropriate.   All 
data will nonetheless be generated and summarized with the goal of publication.  In a highly 
exploratory manner, we will report the data described below within the context of study arm 
assignment; however, comparisons between arms will not be presented as primary outcome 
data but as highly exploratory, non-primary, non-secondary analyses. 
 
Definition of Endpoints.  All patients will undergo a sniff test at baseline, 2 weeks ,  4 weeks and 
at 8 weeks.  As described earlier, patients will be asked to perform the test 10 times; the best 
and worst measurements will be recorded.   
 
 
Baseline 
(within 14 
days of 
registration to 
study) 
2 weeks 
(+/- 7 days) 
4 weeks (+/- 
7 days) 
8 weeks from 
last visit (+/- 7 
days) 
Total blood 
volume 
history and 
physical 
examination 
 
X 
 
 
X 
 
X 
 
laboratory 
results 
(creatinine, 
bilirubin,  
CDHVD 1,25 
Dihydroxy D2 
and D3,  
transaminase, 
alkaline 
phosphatase) 
 
X 
 
 
 
 
5ml 
SNIP, MIP and 
MEP tests 
X 
X 
X 
X 
 
Laboratory 
results 
Calcium and 
phosphorous 
X 
X 
X 
X 
 
1ml each 
time point 
Questionnaires* 
 
X 
X 
X 
 


Version v.2 09.07.2018 
 
10 
1) Primary endpoint.  These sniff test readings and the descriptive presentation of these data 
will be the primary endpoint of this trial.   
 
2) Secondary endpoint. Patients will also be provided with an adherence questionnaire that they 
will be completed at the end of 8 weeks; this questionnaire has been used extensively by our 
group in prior studies and will serve as a secondary endpoint for this trial [30-32]. 
 
3) Exploratory secondary endpoint.  In view of the fact that an identical placebo can result in 
clinical improvements in 30-40% of cancer patients, we will develop a questionnaire that queries 
patients about which study arm they believe they were assigned [32].  We will present the 
results from this questionnaire descriptively as a percentage with 95% confidence intervals.  
These exploratory findings will be of value as we plan for a larger, more definitive clinical trial; 
this questionnaire will potentially add preliminary validation to our choice of placebos. 
 
 
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