Clinical trial NCT01754909
Conditions: Lung Cancer Radiation Pneumonitis
Keywords: lung cancer radiation pneumonitis mitigation enalapril placebo
Sponsor: VA Office of Research and Development
Start date: 2013-11-01; Completion date: 2018-04-01
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This project will test the effect of enalapril to mitigate the lung damage that can occur as a side effect of radiation therapy for lung cancer or other intrathoracic cancers. Thousands of Veterans develop lung cancer every year, and are treated by radiation therapy. Studies of lung radiation injury in laboratory animals show that with enalapril, investigators can significantly reduce the severity of radiation injury to the lung. Enalapril is FDA approved and in common use for treatment of hypertension, kidney disease, and heart failure. These studies will advance that work to human use. Successful mitigation of lung radiation damage will improve the quality of life in Veterans and non-Veterans who are treated for lung cancer by radiation, and may also improve cure rates of radiation therapy for lung cancer.

Detailed description:
Aim 1: To test the benefit of enalapril, an angiotensin-converting-enzyme-inhibitor, to mitigate radiation pneumonitis and fibrosis in humans.

Subjects

Men and women undergoing radiation therapy for lung cancer or other intrathoracic cancers at the Baltimore the Milwaukee or Ann Arbor Veterans Affairs Hospital are eligible. Subjects will be recruited to this phase 2 trial after their diagnosis of cancer and after referral to Radiation Oncology for treatment. The existence of this study will be posted in the Radiation Oncology clinics. Dr Cohen, Dr Beth Gore, and Dr Michelle Mierzwa (co-investigators) and our study coordinators will ensure recruitment. The informed consent process will be done by Dr Cohen or Gore or Dr Mierzwa or the study coordinators. Subjects who require radiation therapy to attempt to cure or to palliate their disease will be eligible for this study. Subjects eligible for surgical resection and who do not need radiation therapy will not be eligible for this study. Subjects on ACE inhibitors, angiotensin blockers, or renin antagonists will be excluded. Use of other antihypertensives is not an exclusion criterion. There will be no inclusion or exclusion by race or ethnic origin. Women and minorities are eligible. Children are not eligible because children do not develop lung cancer. Previous surgery and past or current use of chemotherapy are not exclusions. Subjects will have a Karnofsky performance status \>/=70, absolute neutrophils \> 1000/mm\^3, platelets \> 75,000/mm\^3, and hematocrit \> 25%. Liver and kidney function tests will be within normal range and baseline blood pressure will be systolic \> 110 mmHg sitting. Pregnant or nursing subjects are excluded and fertile patients will use contraception. Lung function tests including spirometry, lung volumes and diffusing capacity will be obtained as part of standard of care for patients prior to radiotherapy, but indices from lung function tests will not be a cause for exclusion.

The mean lung dose will be \>/= 18 Gy and/or V20 \>20%. Radiation will be delivered with standard fractionation schedule of 1.8 to 2 Gy per day, 5 days per week, without planned treatment breaks.

Experimental design

Radiation treatment starts at time 0, and is given to completion, as indicated. Enalapril or placebo are started after the first radiation treatment fraction and continued thereafter. The renin-angiotensin system is tested at time 0, at three weeks, and at the completion of radiation treatment. CT scanning is done at time 0 and every three months thereafter for the first two years. Median survival is expected to be 18 months.

Subjects will undergo therapeutic irradiation as indicated for clinical care. They will be enrolled to this masked, phase 2 trial at the start of radiation therapy (RT), stratified for cancer stage, then randomized to enalapril or identical-appearing placebo. Randomization will be done by the Department of Biostatistics, Medical College of Wisconsin, using random number tables; the center pharmacies will be notified of the assignment to enalapril or placebo. There will be no stratification by age, gender, lung cancer histology, or use of chemotherapy since these do not have a consistent relation with the occurrence of RP . Use of enalapril or placebo will not be known to the patients or their physicians during the time of study. The medical center pharmacy will stock and provide the study drug. Study drug, enalapril or placebo, will be started after the first fraction of the RT, at 2.5 mg by mouth once a day and increased to 10 mg/day in weekly increments as tolerated. Routine clinical care during the course of irradiation includes weekly or more frequent clinical assessment and vital signs. Blood testing for kidney function and potassium will occur within ten days after start of study drug. Additional patient visits will not occur for this study alone. Additional blood testing will occur in usual clinical care and will also be recorded. Routine care, independent of this study, includes CT scan chest imaging every three months for the first two years of follow-up. The study drug will be continued for life.

Endpoints for injury

The primary endpoint is symptomatic grade 2 or higher radiation pneumonitis, as defined by the established criteria, within the first 4 months of irradiation. The NCI Common Terminology Criteria Adverse Event (CTCAE) version 4.0 will be used to grade pulmonary toxicity. CTCAE is a worldwide standard for reporting adverse events from all modalities on cancer clinical trials. Pneumonitis is a new-onset and persistent cough requiring anti-tussive agents and or dyspnea with effort that is unexplained by other pulmonary illness. It may last for days to weeks. Severe cases may evolve to respiratory failure. Use of such patient-reported symptoms is strongly recommended for cancer-related clinical trials. Radiographic changes of RP occur in over half of subjects undergoing therapeutic thoracic irradiation; radiographic RP will be a secondary endpoint. Classic radiographic manifestations of RP are increased lung density within the radiation field within the first six months after radiation therapy that is not explained by infection or cancer. radiographic pneumonitis will be recorded by two investigators (Drs Gore and Antonescu-Turcu, EG, AAT), using the scale reported by Guckenberger. Investigators expect a radiographic rate of RP of 50%.

Investigators expect almost all surviving subjects to have fibrosis by CT scanning at 6 and 12 months, and will test this as another major endpoint. Radiation fibrosis in the lung is evident as scarring with volume loss and bronchiectasis within the radiation field at six months or more after radiation therapy, not explained by infection or cancer. radiographic fibrosis will be recorded and quantified by two investigators (EG, AAT). Reduction in diffusion capacity for carbon monoxide (DLCO) correlates with pulmonary radiation fibrosis. DLCO is obtained in all survivors at the 12 month time point, and will be compared to baseline values as an additional secondary endpoint. The occurrence of clinical grade 2 or higher RP, of radiographic RP and fibrosis as dichotomous variables, will be compared for the subjects on enalapril compared to those on placebo. For RP, any image showing RP will assign a subject to the RP group. For fibrosis, the last CT scan will be used.

Investigators will test quality of life as a secondary endpoint. The Functional Assessment of Cancer Therapy -lung (FACT-L version 4) will be used to assess Quality of Life (QoL). FACT-L contains four general (physical, social/family, emotional, and functional well being) and one lung cancer specific subscale. QoL will be assessed pretreatment, and at 12 months post treatment. Use of patient-reported data is strongly recommended for cancer-related clinical trials.

Aim 2: To test the mechanism of mitigation by enalapril

Subjects These are the same subjects as in aim 1.

Experimental design Investigators will test the major components of the renin-angiotensin system; angiotensinogen, plasma renin activity, and angiotensin II (ang II). These will be measured at baseline, at three weeks after the start of irradiation, and at the completion of irradiation. Investigators will test their mechanistic involvement by their change with use of enalapril, in particular whether the benefit of enalapril is correlated with its effect to lower the plasma ang II levels. Other components of the RAS, including angiotensin (1-7), aldosterone, AcSDKP, and bradykinin will not be tested because experimental studies have not shown them to be relevant to mitigation of normal tissue radiation injury.

Baseline elevation of one or more of these RAS components, compared to known levels in the normal population, may correlate with development of RP and or fibrosis in the control, placebo group. This may permit better focused use of mitigators in the future, in only those at risk.

Enalapril, by inhibition of ACE, will reduce plasma ang II and lead to a feedback elevation of PRA. This will confirm adherence to drug therapy and may also correlate with its benefit. Elevation of PRA in subjects on enalapril, but without mitigation benefit, will show that it is ineffective, despite its adequate bioavailability.

Aim 3: To confirm that enalapril does not adversely affect cancer treatment outcomes.

Subjects These are the same subjects as in aim 1.

Experimental design Investigators will compare cancer recurrence and cancer-related survival in subjects on enalapril versus placebo. Cancer recurrence will be assessed clinically, as confirmed by CT imaging and or histology. The RECIST criteria will be used. Recurrence rates and survival will be assessed by interim safety analyses during the study, and finally at its completion. In the statistical analysis, investigators will account for the effects of interim sampling for the safety analyses, and will adjust for patient and disease characteristics as well as missing data. A benefit of enalapril on RP may enhance patient survival. An adverse effect of enalapril on survival will stop this study. But a cohort of 162 Veterans showed no difference in patient survival for those on ACE inhibitor compared to those not on ACE inhibitor. Thus, investigators do not expect adverse changes in recurrence rates or patient survival.

Expected results, potential problems, and long-term impact

Investigators expect that subjects on enalapril will have significantly less clinical and radiographic RP and fibrosis, compared to those on placebo. Investigators expect that subjects on placebo who develop RP and or fibrosis may have baseline elevation of AGT and PRA compared to those who don't develop RP and or fibrosis, and that the mitigation benefit of enalapril will correlate with its effect to increase the PRA and reduce the plasma ang II levels. Investigators expect that enalapril will not increase cancer-related mortality, and may even enhance overall patient survival through mitigation of radiation lung injury.

Arms: arm 1: Use of enalapril in subjects undergoing radiotherapy for lung cancer. arm 2: Use of placebo in subjects undergoing radiotherapy for lung cancer
Interventions: intervention 1: Enalapril intervention 2: placebo
Intervention descriptions: intervention 1: Enalapril once a day, orally, as 2.5 , 5, or 10 mg tablets to be given in escalating doses, to subjects undergoing radiotherapy for lung cancer intervention 2: Placebo, once a day, orally, as 2.5 , 5, or 10 mg tablets to be given in escalating doses, to subjects undergoing radiotherapy for lung cancer

Protocol documents:
Prot_000.pdf: 
Cover page  
 
Title: Mitigation of radiation pneumonitis and fibrosis 
 
ClinicalTrials.gov Identifier: NCT01754909 
 
Most recent IRB approval Nov 13, 2017 
 
 
 
 
Protocol for “Mitigation of radiation pneumonitis and fibrosis” 
 
Cohen VA 1531-01, CLIN-004-12S 
 
Original from Oct 31, 2012 Registration packet, incorporating amendments through July 2015 
 
 
 
Objective 
 
This project will test the effect of enalapril, an angiotensin-converting-enzyme inhibitor, to 
mitigate radiation pneumonitis and fibrosis in veterans undergoing radiation therapy for lung 
cancer and other cancers in the chest. It is based on the hypothesis that human normal tissue 
radiation injury can be safely and effectively mitigated, and on our extensive studies of 
radiomitigation in experimental animals. Lung cancer is more common in veterans than in the 
general population; this project is highly relevant to the medical care of veterans. 
 
Research design and methodology 
 
 Enalapril or placebo will commence after the start of irradiation in veterans undergoing radiation 
therapy for lung cancer and other cancers in the chest, and their effects on radiation 
pneumonitis and fibrosis will be compared as the primary outcome measure. Enalapril will be 
used rather than captopril, because enalapril is given in single daily doses. This is a 
prospective, double-blinded, randomized, placebo-controlled trial, in a secondary-tertiary care 
setting. Subjects will join this trial voluntarily, based on their planned radiotherapy for lung 
cancer, and it is planned to enroll 200 subjects over the five years of this study. The intervention 
of this study is the use of enalapril or placebo, which will be maintained for the lifetime of the 
study subject. 
 
2.    To test the mechanism of mitigation of radiation lung injury by enalapril. 
        a. Angiotensinogen, plasma renin activity, and angiotensin II will be measured as renin-
angiotensin system markers in all subjects. 
        b. The effect of enalapril on each marker will be assessed, as compared to placebo. 
 
3.    To confirm that enalapril in this use does not adversely affect cancer treatment outcomes. 
        a. Cancer recurrence and death from cancer will be compared for the enalapril and 
placebo groups. 
 
These studies will be done in men and women undergoing radiation therapy for lung cancer and 
other cancers in the chest. Enalapril, or identical-appearing placebo, will be started within a day 


to up to 30 days of the beginning of the radiation treatments. The effect of the enalapril or 
placebo will be tested by their effect to reduce grade 2 or greater clinical radiation pneumonitis, 
by their effect on the renin-angiotensin system markers angiotensinogen, plasma renin activity, 
angiotensin II, and their effect to reduce radiographic evidence of pneumonitis and fibrosis. 
 
 
 
 
 
 
 
 
 
 
NARRATIVE SUMMARY - HUMANS 
 
 
 
1. 
PURPOSE.  Provide the purpose or objectives of the study.  Do not indicate "N/A" for 
this category. 
To test the benefit of enalapril, an angiotensin-converting-enzyme-inhibitor, to mitigate 
radiation pneumonitis and fibrosis in humans. 
 
2. 
SCIENTIFIC RATIONALE.  Provide the reasons for doing the study.  Do not indicate 
"N/A" for this category. 
This project will test the effect of enalapril, an angiotensin-converting-enzyme inhibitor, to 
mitigate radiation pneumonitis and fibrosis in veterans undergoing radiation therapy for lung 
cancer and other cancers in the chest. It is based on the hypothesis that human normal 
tissue radiation injury can be safely and effectively mitigated, and on our extensive studies 
of radiomitigation in experimental animals. Lung cancer is more common in veterans than 
in the general population; this project is highly relevant to the medical care of veterans. 
 
 
3. 
BACKGROUND.  Provide information from previous studies leading up to this study, 
either from your laboratory or from those of others.  If this is a treatment study involving 
investigational drugs, devices, or therapies, standard treatment must be clearly identified.  Do 
not indicate "N/A" for this category. 
Lung cancer is an important health problem for veterans. It is more common in them than in 
the general population, and lung cancer survival is less in veterans. Radiation therapy for 
lung cancer is used in over half of the cases, and it can be followed by radiation 
pneumonitis and fibrosis. These add significant morbidity and mortality, and they limit the 
doses of curative irradiation. Standard treatments for radiation pneumonitis and fibrosis are 
very limited. Mitigation is a new approach, being the use of an agent after initial irradiation 
but before the expression of radiation injury.  
Our studies in rats show significant mitigation of radiation pneumonitis and fibrosis by 
angiotensin converting enzyme (ACE) inhibitors.  
Our recent clinical trial shows the mitigation of radiation nephropathy by the ACE inhibitor 
captopril.   
Our retrospective clinical studies show that concurrent use of ACE inhibitors reduces the 
occurrence of radiation pneumonitis [and fibrosis], without lowering cancer-related survival.  
The safe mitigation of radiation injury has been identified as a priority by the National 


Cancer Institute. We will address this critical problem. We hypothesize that the occurrence 
of radiation pneumonitis, fibrosis, or both in patients receiving radiation for lung cancer will 
be decreased by the ACE inhibitor enalapril, started after irradiation. 
 
 
4. 
STUDY DESIGN.  Provide a brief description of the design of the study (multicenter, 
double-blind, randomized, etc.) in narrative form.  Do not provide details of specific procedures 
in this section (see Item 9 below).  Include, as needed, a discussion of the appropriateness of 
research methods.  Describe the statistical design and required sample size.  Do not indicate 
"N/A" for this category. 
 
This is a prospective, double-blinded, randomized, placebo-controlled trial, in a secondary-
tertiary care setting. The ZVAMC and referring VAs in VISN 12 are the main centers; the 
Baltimore VAMC will be added,. Subjects will join this trial voluntarily, based on their 
planned radiotherapy for lung cancer. We will enroll 200 subjects over the five years of this 
study. Statistical power analysis suggests the need for 200 subjects for the clinical 
endpoint, and ~ 100 subjects for the radiographic endpoint. 
 
5. 
SUBJECT SELECTION AND EXCLUSION CRITERIA.  Provide the specific criteria for 
including and excluding subjects in the study.  Do not indicate "N/A" for this category. 
 
Men and women undergoing radiation therapy for lung cancer and other cancers in 
the chest at the Milwaukee VAMC and the Baltimore VAMC are eligible. Subjects 
will be recruited to this phase 2 trial after their diagnosis of cancer and after referral 
to Radiation Oncology for treatment. The existence of this study will be posted in 
the Radiation Oncology clinics. Subjects who require radiation therapy to attempt to 
cure or to palliate their disease will be eligible for this study.  Subjects eligible for 
surgical resection and who do not need radiation therapy will not be eligible for this 
study. Subjects already on ACE inhibitors, angiotensin blockers, or renin 
antagonists will be excluded, but may participate if these medications are stopped 
by their treating physicians before the start of their participation in this study. 
Subjects with past history of allergy to ACE inhibitors will be excluded. Use of other 
antihypertensives is not an exclusion criterion. There will be no inclusion or 
exclusion by race or ethnic origin.  Women and minorities are eligible. Children are 
not eligible because children do not develop lung cancer. . Previous surgery and 
past or current use of chemotherapy are not exclusions. Subjects will have a 
Karnofsky performance status ≥70, absolute neutrophils > 1000/mm^3, platelets > 
75,000/mm^3, and hematocrit > 25%. Liver and kidney function tests will be within 
normal range, alkaline phosphatase up to 1.2 and serum creatinine up to 1.1 times 
upper limit of normal, and baseline blood pressure will be systolic > 110 mmHg 
sitting. Pregnant or nursing subjects are excluded and fertile patients must have a 
negative pregnancy test and will use contraception. Lung function tests including 
spirometry, lung volumes and diffusing capacity will be obtained as part of standard 
of care for patients prior to radiotherapy, but indices from lung function tests will not 
be a cause for exclusion. 
 
6. 
SUBJECT POPULATIONS.  Indicate the subject populations to be recruited for the 
study. 


Provide scientific and ethical justification for use of any vulnerable subject populations or other 
potentially vulnerable subjects defined on page 3 and outline additional safeguards planned to 
protect their rights and welfare.  If no additional safeguards are required, provide a justification.  
Provide a scientific and ethical justification for exclusion of women or minorities or other classes 
of subjects who might benefit from the study.  Include a justification for the use of non-veterans, 
if applicable.  Do not indicate "N/A" for this category. 
Note:  Exclusion of pregnant women does not require justification. 
 
Men and women undergoing radiation therapy for lung cancer and other cancers in the 
chest at the Milwaukee VAMC and the Baltimore VAMC are eligible. Vulnerable populations 
will not be recruited. 
 
7. 
RECRUITMENT AND ENROLLMENT PROCEDURES.  Describe the methods used to 
obtain information about individuals who may be recruited to participate in study.  Indicate if 
medical records, OR schedules, appointment logs, rounding lists, or procedure posting boards 
will be reviewed to search for potential study subjects.  Address all of the following that apply: 
Financial enrollment bonuses to investigators personally or added to study budget for fast 
enrollment or for additional numbers of subjects.   
Additional financial or non-financial incentives offered by the sponsor.   
If a multi-center trial, whether there is competition between sites to fill available subject slots on 
a first-come, first-serve basis, and whether this affects authorship on journal articles.  
Identification of eligible patients from investigators' own patient pools and how coercion will be 
avoided.   
Referrals from local physicians and whether fees will be offered.   
Distribution of study information for subject recruitment purposes to appropriate disease 
advocacy groups, student groups, or local community organizations, perhaps by giving lectures 
or presentations or at health fairs or medical screenings.   
Use of advertising and whether ads will be used within the ZVAMC or in newspapers, radio, 
television, or on Internet sites.  Attach all advertising to protocol.  
 
Submit "Request for Waiver of Subject Authorization" as appropriate.  See "HIPAA" at the 
beginning of this packet. 
 
The existence of this study will known to Radiation Oncology staff. At Milwaukee, Dr Gore 
(co-investigator) and her study coordinator will ensure recruitment. At Baltimore, Dr 
Jackson and his staff will ensure recruitment. Non-participation in this study will not affect 
the clinical care of the patient. 
 
8. 
INFORMED CONSENT PROCEDURE.  Describe the circumstances surrounding the 
consent procedure, including setting and whether privacy interests are protected during the 
consent procedure, subject autonomy concerns, language difficulties, vulnerable populations, 
and other details.  Include the procedures for assessing the subject’s capacity to consent.  
Outline the procedures for ensuring sufficient opportunity for subjects to decide, and the 
procedures to ensure that subjects give consent without coercion.  Describe the procedures for 
documentation of informed consent, including chart documentation, using witnesses, 
translators, and document storage.  Indicate the procedures for informing subjects of new 
findings. 
 
(Please also read "Obtaining Informed Consent" at the beginning of this packet.) 
 


Waiver of informed consent requires completion of a "Request for Waiver of Informed Consent" 
form and a "Request for Waiver of Subject Authorization." 
Waiver of documentation of informed consent requires completion of a "Request for Waiver of 
Documentation of Informed Consent" form and an information sheet (format on our web site). 
 
The consent procedure takes place in the Radiation Oncology clinics at the ZVAMC or the 
Baltimore VAMC. Privacy and autonomy will be ensured by standard clinical practice. The 
purpose of the study, the procedures of the study, its risks and benefits, and alternatives 
will all be explained as part of the consent process. Vulnerable populations will not be used. 
Assessment of capacity to consent will be identical to assessment of capacity to consent to 
usual treatment, including radiation treatment. This includes assessment of orientation and 
understanding of risk and benefit. Subjects will be able to view the consent form in writing, 
will be able to ask questions of the coordinator and the co-investigator, and will not be 
coerced. Documentation will be in writing and will be stored on the VA CPRS record. 
Witnesses will participate as required. The coordinator and co-investigator have ample 
experience with clinical studies and will adhere to their existing high standards for securing 
consent. New findings will be communicated to all study participants when these findings 
are available. 
 
Names and qualifications of those obtaining informed consent.   
 
Dr Elizabeth Gore, Radiation Oncologist, Milwaukee 
Joseph Berman, Study coordinator, Milwaukee 
 
Dr Eric Cohen, Medicine, Baltimore 
 
 
9. 
PROCEDURES.  REVISED   Describe all procedures involving the participation of 
human subjects, chart review, or collection of samples.  Provide details.  Include the location 
where the study will take place.  Do not indicate "N/A" for this category. 
 
If the protocol involves "usual care," you must clearly differentiate the research intervention(s) 
from "usual care" (whether the "usual care" is limited to one arm of the study or is being 
delivered to all study subjects).  You must also clearly designate the individual or entity (e.g., the 
appropriate research personnel vs the subject's health care provider) responsible for relevant 
aspects of both the research and the "usual care." 
 
The study drug, enalapril or placebo, will be in addition to usual clinical care of 
subjects undergoing radiation therapy for lung cancer. Enalapril, or placebo, will be 
given orally, started within a day to up to 30 days of the beginning of the radiation 
treatments. They will be enrolled at the start of radiation therapy (RT), stratified for cancer 
stage, then randomized to enalapril or identical-appearing placebo. Randomization will be 
done by the Department of Biostatistics, Medical College of Wisconsin, using random 
number tables; the center pharmacies will be notified of the assignment to enalapril or 
placebo. There will be no stratification by age, gender, lung cancer histology, or use of 
chemotherapy since these do not have a consistent relation with the occurrence of RP. 
There is no stratification by center. Study drug is obtained from Expert Pharmacy Inc, with 
identical appearing enalapril and placebo tablets. It is held in the VA research pharmacy at 
Milwaukee, in a restricted access area under the aegis of the research pharmacist.It will be 
sent to patients at the Baltimore site upon their enrollment. The study drug dose will be 


2.5 mg to start, and will be increased in increments of 2.5 mg to 10 mg per day, as 
tolerated. Clinical follow up of study subjects will be identical to that of subjects 
undergoing radiation therapy for lung cancer but who are not participating in this 
study, with the addition of four blood samples. One blood sample one week after 
starting the study will be to check for adverse effects of the study drug. Three more 
blood samples will be obtained for renin-angiotensin system (RAS) assays, done on 
three blood samples from each subject, at the start of the study, at 3 weeks after 
the start, and at the end of radiation therapy. Each of these four research-related 
blood samples will be approximately one teaspoon of blood obtained by 
venipuncture. Compliance is assessed by monitoring the requests for study drug 
refills. It will be verified at the end of the study by the elevation in plasma renin in 
subjects on enalapril compared to those on placebo. Study subjects will be 
monitored for adverse effects of study drug.  The development, or not, of radiation 
pneumonitis and fibrosis will be assessed in the study subjects, as part of ongoing 
regular care, as are the periodic radiographic imaging and lung function testing.  
Quality of life will also be assessed. 
 
10. 
RISKS AND PRECAUTIONS.  Provide a description of all risks (physical, psychological, 
social, legal, and/or economic) for each drug or procedure used.  Indicate how risks will be 
minimized, including a description of procedures already being performed on the subjects for 
diagnostic or treatment purposes that will be used.  Provide a description of these procedures. 
Distinguish risks associated with research from risks of therapies subjects would receive 
even if not participating in research.  Include precautions to be taken to minimize the danger 
and/or pain.  Provide a plan for notifying subjects of new findings that may affect their 
willingness to participate in the project.  If there are no risks to participating in the study, this 
should be stated.  Do not indicate "N/A" for this category. 
 
Investigational devices:  Include the risks of procedures involved in the use of investigational 
device and risks of investigational device compared to risks of alternative devices or 
procedures.  
 
Enalapril is an angiotensin-converting-enzyme inhibitor in common use, for treatment of 
hypertension, kidney disease, and heart failure. It is used to lower blood pressure, and is 
also used in normotensive subjects with heart failure.  Subjects with normal blood pressure 
who would use enalapril to mitigate radiation injury could develop low blood pressure which 
could cause dizziness and drug intolerance. This will be avoided by starting with low doses 
and increasing the drug dose, as tolerated. Elevation in serum potassium could occur; we 
will test for this in one extra blood sample, and monitor for it in subsequent usual clinical 
follow-up. Between 2 and 5% of subjects using enalapril could develop a cough, which 
resolves within a few days of stopping the drug. Intolerable cough will lead us to stop the 
study drug.  The safety of enalapril in this use is very likely, because we have documented 
the safe use of lisinopril, another angiotensin-converting enzyme inhibitor and a congener 
of enalapril, in veterans at ZVAMC undergoing radiation therapy for lung cancer. These 
were subjects already on lisinopril when they underwent radiation therapy for lung cancer. 
We found no adverse effects of this use of lisinopril. In another study, we used captopril 
compared to placebo in bone marrow transplant patients, to mitigate chronic renal failure. 
There was no difference in drug tolerance in patients on captopril compared to those on 
placebo. 
The therapeutic risk is that of the medical care by, during, and after radiation therapy for 


lung cancer. The research risk is that of the use of the study drug, enalapril or placebo, as 
detailed above. There is also the risk of obtaining blood for RAS studies. There is no 
alternative to the therapeutic risk, for subjects undergoing radiation therapy, because it is 
the standard of care for those subjects. The alternative to the research risk is to not 
participate in this study. The alternative is to undergo usual and customary care, by 
radiation therapy for the patient with lung cancer. 
Data security and confidentiality will be maintained according to the rules of the Department 
of Veterans Affairs. Risks to breach of privacy and confidentiality will thereby be avoided.  
All data for this study will only be stored on password-protected VA computers. Data 
collection for complications of treatment, adverse and severe adverse events will be done 
by a dedicated study coordinator who will prospectively track all of the subjects of this 
study. 
 
 
11. 
ANTICIPATED BENEFITS OF THE STUDY AND RISK/BENEFIT ASSESSMENT.   
Describe the benefit to the subject and/or benefit to science. State if subjects will receive no 
benefit. 
 
Investigational devices:  Benefits of investigational device compared to benefits of alternative 
devices or procedures. 
 
Subjects in this study may have a fifty percent or more reduction in the occurrence of 
radiation pneumonitis. Based on pre-clinical data in laboratory animals, we expect that to 
occur in subjects on enalapril compared to subjects on placebo. But this is not known or 
guaranteed, which is why this study of enalapril compared to placebo must be done. Based 
on extensive use of enalapril for other indications, and on our study of its congener, 
lisinopril, in veterans undergoing radiation therapy for lung cancer, the risks of this study 
related to use of study drug are small, and reasonable in relation to the anticipated benefits 
to subjects and others. 
 
 
The broad, long-term objective of our work is to achieve effective and safe mitigation of normal 
tissue radiation injuries for any tissue type. We and others have successfully mitigated normal 
tissue radiation injury (NTRI) of kidneys, lungs, skin, and brain, using laboratory rat models. The 
success of these human studies will have a high impact for subjects at risk of NTRI to the lungs. 
This will improve the health of veterans with lung cancer, which is highly relevant to the mission 
of the Department of Veterans Affairs. That success will be a significant impetus to extend the 
radiomitigation concept to other normal tissues at risk during radiation therapy, such as spinal 
cord or brain. 
 
12. 
DATA SAFETY MONITORING.  REVISED   A data and safety monitoring plan is 
required for all interventional clinical research protocols that involve more than minimal risk to 
subjects.  Provide the following information: 
 
a. 
The type of data or events to be captured under the monitoring plan, including SAEs, 
and how will safety information be collected (e.g., with case report forms, at study visits, by 
telephone calls with subjects).   
b. 
Who will be responsible for monitoring the data collected (investigators, sponsor, a 
coordinating or statistical center, an independent medical monitor, a data safety monitoring 
board (DSMB) or data monitoring committee (DMC), or some other entity)? If there is a data 
safety monitoring board (DSMB), describe its composition and indicate if it is 


independent of the sponsor. If no DSMB, provide the statistical tests for analyzing the safety 
data to determine if harm is occurring. 
c. 
Procedures for communicating to the IRB, the sponsor, and other appropriate entities 
the outcome of the reviews by the monitoring entity. If DSMB reports will be forwarded to the 
IRB, include the interval they will be submitted.  Members of DSMBs/DMCs are encouraged to 
complete human subjects research training. 
d. 
Process for monitoring and reporting adverse events and unanticipated problems to the 
monitoring entity and IRB, and include the time frames for reporting these events.  Include the 
following statement: Unanticipated problems involving risks to subjects or others (UAPs), 
internal serious adverse events (SAEs), and protocol deviations/violations will be reported to the 
IRB using the local reporting form within 5 days of notification of the event. 
e. 
The frequency of data collection and assessments of data or events captured by the 
monitoring plan, such as points in time or after a specific number of participants are enrolled. 
f. 
The definition of specific triggers or stopping rules that will dictate when some action is 
required (e.g., studies may be stopped when there is a greater than expected rate of morbidity 
or mortality or when the experimental arm of a head to head comparison study is shown to be 
better or worse statistically than the standard care arm). 
 
For retrospective studies, include whether or not you will discuss with the subjects 
potential study outcomes that may have an effect on their health or well being and when 
and how you will notify individual subjects or their health care providers of these 
findings. 
 
***Additional information is provided in “Data Safety Monitoring Plans” at the beginning of this 
packet*** 
 
 
a. 
Data or events to be captured included the development of adverse reaction s to 
study drug, including cough, low blood pressure, elevation in serum potassium, fall in white 
blood cell count, or red blood cell count (anemia). It is estimated that each of these have a 
risk of less than 5%. This information will be collected at study visits, upon report by study 
subject, will be documented on report forms, and will be verified by monthly chart reviews 
for all active subjects on this study. Serious adverse events (SAE) are those that cause 
significant morbidity or threat to life.  
b. 
Investigators and the study coordinator will be responsible for monitoring the data 
collected, and will report safety data to a central VA DMSB, the Data Monitoring Committee 
(DMC) at Hines VAMC, upon enrollment of 50, 100, 150 and 200 subjects.  
c. 
DSMB reports will be forwarded to the IRB at least yearly. 
d. 
Unanticipated problems involving risks to subjects or others (UAPs), internal serious 
adverse events (SAEs), and protocol deviations/violations will be reported to the IRB and 
the DMC using the local reporting form within 5 days of notification of the event. 
e. 
The data collection will be continuous. The safety assessments will be upon 
enrollment of 50, 100, 150, and 200 subjects. 
f. 
Studies will be stopped when there is a greater than expected rate of morbidity or 
mortality or when the experimental arm of a head to head comparison study is shown to be 
better or worse statistically than the standard care arm, taking into account any multiple 
comparison statistical issues. 
 
 
13. 
COMPENSATION OF SUBJECTS.  Provide the terms of the subject participation 
agreement and the amount of payment.  Substantiate that proposed payments are reasonable 


and commensurate with expected contributions of the subject and that they do not constitute (or 
appear to constitute) undue pressure on the subject to volunteer for the research study.  
Describe any non-VA compensation for injured research subjects. 
 
No compensation will be provided 
 
14. 
PRIVACY.  Provide provisions to protect the privacy interests of subjects.  Indicate that 
all research personnel will respect the dignity, cultural, psychosocial, spiritual and personal 
values, beliefs, preferences, and personal privacy of research subjects as outlined in Medical 
Center Memorandum 00-102.  In every subject encounter, members of the research team must 
be sensitive to the subject's gender, cultural, psychosocial, spiritual and personal values, beliefs 
and preferences, and how the subject may interact with the procedure to be performed, 
especially if the procedure involves intimate physical aspects.  Personal privacy includes pulling 
cubicle curtains around a bed, closing the room door while providing care or interviewing a 
subject, providing auditory privacy, knocking on a room door before entering, covering the 
subject appropriately both in privacy and in public areas, etc. 
 
      All research personnel will respect the dignity, cultural, psychosocial, spiritual and 
personal values, beliefs, preferences, and personal privacy of research subjects as outlined 
in Medical Center Memorandum 00-102.  In every subject encounter, members of the 
research team will be sensitive to the subject's gender, cultural, psychosocial, spiritual and 
personal values, beliefs and preferences, and how the subject may interact with the 
procedure to be performed. Personal privacy includes pulling cubicle curtains around a 
bed, closing the room door while providing care or interviewing a subject, providing auditory 
privacy, knocking on a room door before entering, covering the subject appropriately both 
in privacy and in public areas. 
 
 
15. 
COSTS TO SUBJECTS.  Describe extra costs to subjects for their participation in the 
study.   
Include extra costs to third party payers because of subjects' participation.  Clinic visits for tests 
and procedures over and above standard care should be considered a cost to subjects in terms 
of travel expenses and time off work. 
 
There will be no extra cost to the subject for participation in this study. 
 
16. 
ROLES OF INVESTIGATORS AND RESEARCH STAFF.  New Requirements  Describe 
the protocol-specific duties of all personnel listed on Page 8.  Include scientific training, 
qualifications, degrees and years of experience. 
 
Eric Cohen, MD, Principal investigator. 
Dr Cohen will supervise all aspects of this study. He will organize the planning and 
performance of the study. He will meet monthly or more often with study personnel to 
ensure timely, accurate, and secure data collection. He will ensure reporting of adverse 
events. He is trained in Medicine and Nephrology, has completed a study of captopril to 
mitigate renal disease after bone marrow transplantation, and has a MD degree and 25 
years of experience with clinical investigation. 
Elizabeth Gore, MD, co-investigator. 
Dr Gore will recruit patients to this study in Milwaukee. She will work daily with the study 
coordinator and will ensure the clinical follow up of the patients, including identification of 


adverse events. She is trained in Radiation Oncology, is an active participant in RTOG 
clinical studies, and has a MD degree and over a decade of experience in clinical 
investigation. 
Andreea Antonescu-Turcu, MD, co-investigator, Milwaukee. 
Dr Antonescu-Turcu will enable the radiographic analysis of pneumonitis and fibrosis of the 
study de-identified patients.  She is trained in Medicine and Pulmonary Medicine, has 
ongoing experience in clinical studies being done at the ZVAMC, and has a MD degree and 
over ten years of clinical experience. 
Aniko Szabo, PhD, co-investigator, Milwaukee. 
Dr Szabo will ensure the statistical aspects of this study. She will create the randomization 
tables for study subject enrollment and randomization. She will enable the statistical 
analysis of the data from this study. She will assist in the safety analyses done after 
enrollment of 50, 100, 150, and 200 subjects. She is a PhD statistician, and has abundant 
experience in statistical aspects of clinical studies, with five years of experience in this 
area. 
Brian Fish, lab manager. 
Mr Fish will assist in data organization, analysis, and publication. 
Joseph Berman, study coordinator. 
This coordinator will secure the enrollment of study subjects, under the supervision of Dr 
Gore. The coordinator will keep complete records of each study subject. He will administer 
the quality of life surveys. He will identify and report adverse events to the IRB without 
delay. He will meet at least monthly with the PI, Dr Cohen, to review progress on the study, 
and ensure up-to-date records. 
To be named, study coordinator, Baltimore 
This coordinator will secure the enrollment of study subjects, under the supervision of Dr 
Cohen. The coordinator will keep complete records of each study subject. He will 
administer the quality of life surveys. He will identify and report adverse events to the IRB 
without delay. He will meet at least monthly with the PI, Dr Cohen, to review progress on 
the study, and ensure up-to-date records. 
 
 
 

SAP_001.pdf: 
Cover page 
 
Mitigation of radiation pneumonitis and fibrosis 
 
ClinicalTrials.gov Identifier: NCT01754909 
 
Most recent IRB approval Nov 13, 2017 
 
 
 
 
Statistical methods plan 
 
Power analysis for aim 1 
For the RP endpoint, at an 11% rate of clinical RP, and an 80% mitigation effect, 97 subjects 
are needed per arm for type 1 error of 0.05 and a power of 0.80. The 11% and 80% figures are 
based on our retrospective studies. Only 49 are needed per arm for a baseline clinical RP rate 
of 20%. We plan for 200 subjects because there is variability in the rate of RP, and because we 
cannot be certain about the magnitude of efficacy of enalapril. 
 
For a 50% radiographic rate of RP, and a halving of this by enalapril, 45 subjects are needed 
per arm. 
 


 
For the radiographic fibrosis endpoint, at a 90% fibrosis rate, 29 subjects per arm would identify 
a 30% reduction in radiographic fibrosis at 6 or 12 months. 
 
Endpoint and RAS analyses 
Dichotomous variables will be compared by chi-square, or Fisher’s exact test, as indicated. 
Continuous variables will be compared by parametric or non-parametric statistics, as 
appropriate. Repeated measurements on the effects of enalapril and placebo on [RAS 
components] will be tested by a repeated measures ANOVA for continuous [RAS component] 
values and by a logistic type regression models [using GEE techniques for discrete [RAS 
component] values. In either case appropriate generalized linear models 
methods will be used to account for the association between repeated measurements over time 
on the testing procedure.] We will repeat the analysis using an appropriate regression analysis 
to account for possible patient factors which may influence outcome in addition to enalapril. We 
will also look at a model for RP and fibrosis using enalapril use and the RAS components as 
predictors as well as interactions between drug use and these predictors. Correlations will be 
made using Spearman’s or Kendall correlation, as indicated. Dose modification factors (DMF) 
for the use of enalapril compared to placebo will not be tested since the expected radiation dose 
ranges will be too narrow. A more formal attempt to understand the mechanism of enalapril 
action on RP and fibrosis and determine if this is possibly derived through any one of the [RAS 
components] will use a structural equation modeling approach. This approach uses a matrix of 
regression coefficients from a series of regression models [of intermediate effects at the various 
time points to other intermediate effects at the same time point or to future intermediate or 
terminal effects. Using these coefficients and a postulated causal diagram which depicts which 
effects may be dependent on the patient history at a given time]. A final causal diagram which 
shows the relationship between drug, intermediate outcome and RP and or fibrosis [is 
constructed]. Path analysis techniques to construct the causal diagram can be constructed 
using the program DIGRAM (53). [This cited reference shows how this approach works by 
looking at causal factors for heart disease using data on behavioral factors measured at epochs 
in time.] 
 
Survival analysis for aim 3 
Cancer-related survival and cancer recurrence will be compared for the enalapril and the 
placebo groups using Kaplan-Meier statistics. [We have calculated our ability to detect 
significant changes in cancer recurrence rates and in cancer survival, both for improvements in 
cancer-related outcomes and for adverse trends. We will be able to detect significant increases 
in recurrence rates or mortality. Our cohort of 162 subjects showed no difference in patient 
survival for those on ACE inhibitor compared to those not on ACE inhibitor. We do not 


expect adverse changes in recurrence rates or patient survival. A mitigation benefit by enalapril 
could lead to an increase in patient survival, but less than a three month increase is not likely to 
be detected] 
 
  
 
[There are potential pitfalls in the recurrence and survival analyses. These include the effects of 
interim sampling for the safety analyses, and adjustments for patient and disease characteristics 
as well as missing data. ] The interim masked safety analyses will use the O’Brien correction to 
take into account the multiple analyses. In our analysis of survival, we will compare the 
recurrence-free survival rates between the treatment arms of the study in two ways. First we will 
examine the rates of death or recurrence using a Cox model. In this model we will adjust for 
patient/disease characteristics such as site of treatment, gender, age, stage of disease at 
randomization, and radiation dosage. We will also compare the disease free survival 
probabilities at two years using techniques that we have published (52).This method allows us 
to deal with the partial information available in patients who do not have a potential follow-up 
time of two years. This approach, which is a censored data version of logistic regression, will 
allow us to adjust the comparisons for patient, disease, and treatment factors. We picked two 
years here since the empirical evidence is that the disease-free survival 
curves tend to flatten out at around 20 months.