Mitigation of Radiation Pneumonitis and Fibrosis

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Department of Veterans Affairs
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT01754909
First received: November 29, 2012
Last updated: July 22, 2014
Last verified: July 2014
  Purpose

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. 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.


Condition Intervention Phase
Lung Cancer
Radiation Pneumonitis
Drug: Enalapril
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Prevention
Official Title: Mitigation of Radiation Pneumonitis and Fibrosis

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Radiation pneumonitis [ Time Frame: one year ] [ Designated as safety issue: No ]
    The clinical occurrence and grade of radiation pneumonitis, by National Cancer Institute Common Terminology Criteria Adverse Event grading ( NCI CTCAE)


Secondary Outcome Measures:
  • Radiation pneumonitis [ Time Frame: one year ] [ Designated as safety issue: No ]
    The occurrence and grade of radiation pneumonitis by radiographic criteria, using CT scanning

  • Radiation fibrosis [ Time Frame: one year ] [ Designated as safety issue: No ]
    The occurrence and grade of radiation fibrosis by radiographic criteria, using CT scanning

  • Cancer recurrence and cancer-related survival [ Time Frame: two years ] [ Designated as safety issue: Yes ]
    The recurrence of lung cancer after radiation therapy and the cancer-related survival after radiation therapy, in subjects taking enalapril compared to those on placebo drug.


Estimated Enrollment: 200
Study Start Date: November 2013
Estimated Study Completion Date: January 2020
Estimated Primary Completion Date: January 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: enalapril
Use of enalapril in subjects undergoing radiotherapy for lung cancer.
Drug: Enalapril
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
Placebo Comparator: placebo
Use of placebo in subjects undergoing radiotherapy for lung cancer
Drug: placebo
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

  Hide Detailed Description

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 at the Milwaukee 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 Beth Gore (co-investigator) and her study coordinator will ensure recruitment. The informed consent process will be done by Dr Gore or the study coordinator, under direction of Dr Gore. 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 >25%. 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 right 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 and 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.

  Eligibility

Ages Eligible for Study:   35 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women undergoing radiation therapy for lung cancer at the Milwaukee Veterans Affairs Hospital are eligible.
  • Subjects who require radiation therapy to attempt to cure or to palliate their disease will be eligible for this study.

Exclusion Criteria:

  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01754909

Contacts
Contact: Eric P Cohen, MD (414) 384-2000 ext 42825 Eric.Cohen@va.gov

Locations
United States, Wisconsin
Clement J. Zablocki VA Medical Center, Milwaukee, WI Recruiting
Milwaukee, Wisconsin, United States, 53295-1000
Contact: Joseph E Berman, PT MHS    414-384-2000 ext 42408    joe.berman@va.gov   
Principal Investigator: Eric P. Cohen, MD         
Sponsors and Collaborators
Investigators
Principal Investigator: Eric P. Cohen, MD Clement J. Zablocki VA Medical Center, Milwaukee, WI
  More Information

No publications provided

Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT01754909     History of Changes
Other Study ID Numbers: CLIN-004-12S, 1I01CX000569-01A2
Study First Received: November 29, 2012
Last Updated: July 22, 2014
Health Authority: United States: Federal Government

Keywords provided by Department of Veterans Affairs:
lung cancer
radiation pneumonitis
mitigation
enalapril
placebo

Additional relevant MeSH terms:
Fibrosis
Lung Neoplasms
Pneumonia
Radiation Pneumonitis
Pathologic Processes
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Lung Diseases, Interstitial
Lung Injury
Radiation Injuries
Wounds and Injuries
Enalapril
Enalaprilat
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 24, 2014