Lisinopril in Reducing Shortness of Breath Caused by Radiation Therapy in Patients With Lung Cancer

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01880528
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 23
• Locations: 3
• Arms: 2
• Actual Duration (Months): 68
• Patients Per Site: 7.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This pilot clinical trial studies lisinopril in reducing shortness of breath caused by radiation therapy in patients with lung cancer. Lisinopril may decrease the side effects caused by radiation therapy in patients with lung cancer.

Condition or Disease	Intervention/Treatment	Phase
Dyspnea; Non-small Cell Lung Cancer; Small Cell Lung Cancer	Drug: lisinopril; Drug: placebo	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To explore the adverse event profile of lisinopril, during and after external beam radiation therapy (RT) to the lung.

SECONDARY OBJECTIVES:

1. To explore the level of patient-reported acute respiratory distress (dyspnea) during and after external beam RT.

2. To explore the level of patient-reported symptoms during and after external beam RT.

3. To explore the impact of lisinopril treatment on patient quality of life (QOL) during and after external beam RT.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Beginning within 7 days of beginning radiation therapy, patients receive lisinopril orally (PO) once daily (QD) on days 1-7.

ARM II: Beginning within 7 days of beginning radiation therapy, patients receive placebo PO QD on days 1-7.

In both arms, treatment repeats every 7 days for until 3 months after completion of radiation therapy in the absence of disease progression or unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Supportive Care
• Official Title: A Double-Blind Pilot Study to Measure the Effect of Lisinopril vs. Placebo on Pulmonary Distress in Patients Receiving External Beam Radiotherapy to the Lung
• Actual Study Start Date: May 31, 2013
• Actual Primary Completion Date: Jun 5, 2013
• Actual Study Completion Date: Jan 29, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (lisinopril) Beginning within 7 days of beginning radiation therapy, patients receive lisinopril PO QD on days 1-7.	Drug: lisinopril; Given PO; Other Names: Prinivil Zestril
Placebo Comparator: Arm II (placebo) Beginning within 7 days of beginning radiation therapy, patients receive placebo PO QD on days 1-7.	Drug: placebo; Given PO; Other Names: PLCB

Outcome Measures

Primary Outcome Measures

1. Incidence of Grade 3 or Higher Hypotension, Acute Kidney Injury, Allergic Reaction, or Anaphylaxis, as Measured Using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 [Up to 3 months post-radiation therapy]

   Incidence of grade 3 or higher hypotension, acute kidney injury, allergic reaction, or anaphylaxis, as measured using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. Descriptive statistics of frequency (percentage) will be used to summarize adverse event (AE) incidence and severity in the lisinopril and placebo arms separately.

Secondary Outcome Measures

1. Acute Respiratory Distress (Dyspnea), Measured Using of the Maximum Score, at Any Time, of the Shortness of Breath Question (Item #4) on the LCSS (Worst Dyspnea Score) [Up to 3 months post-radiation therapy]

   Acute respiratory distress (dyspnea), measured using of the maximum score, at any time, of the shortness of breath question (Item #4 "How much shortness of breath do you have?") on the Lung Cancer Symptom Scale (LCSS) (Worst Dyspnea Score). The LCSS tool contains 6 major symptoms associated with lung malignancies and their effect on overall symptomatic distress, functional activities, and global quality of life (QOL). The item scale ranges from 0-10 (0 = None; 10 = As much as it could be) where the LCSS scoring algorithm is applied to convert to a 0-100 point scale where 100 is best quality of life (QOL), for comparability. Patient scores range from 0 to 100, where 100 was best QOL (i.e. less pulmonary distress).

2. Experience Shortness of Breath During Exercise as Measured Using Item #3 on the Symptom Experience Questionnaire (SEQ) at Week 4 [At Week 4]

   Experience shortness of breath during exercise as measured using Item #3 ("Over the past week, did you experience shortness of breath when you exercise or exert yourself?") on the Symptom Experience Questionnaire (SEQ) at Baseline. The item scale ranges from 0-10 (0 = Not at all; 10 = As bad as it can be) where the SEQ scoring algorithm is applied to convert to a 0-100 point scale where 100 is best quality of life (QOL), for comparability.

3. Quality of Life (Dyspnea When Climbing Stairs) Assessed Using Item #5 of the European Organization for Research on the Treatment of Cancer Lung Cancer Module Survey (EORTC-QLQ-LC13) at Week 4 [At Week 4]

   Dyspnea when climbing as measured using item #5 ("Were you short of breath when you climbed stairs?") of the EORTC-QLQ-LC13 at Week 4. The item scale ranges from 1-4 (1 = Not at all; 4 = Very Much) where the EORTC-QLQ-LC13 scoring algorithm is applied to convert to a 0-100 point scale where 100 is best quality of life (QOL), for comparability.

4. Total LCSS Score as Measure by the Lung Cancer Symptom Scale (LCSS) at Week 4 [At Week 4]

   Total LCSS score as measured using the Lung Cancer Symptom Scale (LCSS) at Week 4. The item scale ranges from 0-10 (0 = None; 10 = As much as it could be) where the LCSS scoring algorithm is applied to convert to a 0-100 point scale where 100 is best quality of life (QOL), for comparability.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histological confirmation of small cell and non-small cell carcinoma of the lung receiving thoracic radiotherapy > 45 Gy, with volume of lung receiving 20 Gy or more (V20Gy) >= 20%

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

• Absolute neutrophil count (ANC) >= 1500/mm^3

• Platelet count >= 100,000/mm^3

• Hemoglobin > 9.0 g/dL

• Creatinine clearance >= 30 mL/min as calculated using actual body weight and Cockroft Gault formula

• Initial physical exam with systolic blood pressure (BP) of > 100 mmHg and diastolic BP of > 60 mmHg

• Potassium within institutional normal limits

• Sodium within institutional normal limits

• Negative pregnancy test done =< 14 days prior to registration, for women of childbearing potential only

• Ability to complete questionnaire(s) by themselves or with assistance

• Provide informed written consent

• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

• Willing to provide blood samples for correlative research purposes

Exclusion Criteria:

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Other active malignancy =< 3 years prior to registration; EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment (e.g., maintenance or adjuvant chemotherapy or hormonal therapy) for their cancer

• History of myocardial infarction =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

• History of prior radiation therapy treatment to the lungs or thorax

• Existing contraindications to angiotensin-converting enzyme (ACE) inhibitors such as hypersensitivity to ACE inhibitors, bilateral renal artery stenosis, angioedema, or previously documented adverse drug reaction to ACE inhibitors

• Any of the following:

• Pregnant women

• Nursing women

• Men or women of childbearing potential who are unwilling to employ adequate contraception

• Use of ACE inhibitors (including lisinopril) or ACE receptor blockers (ARB) of any kind =< 90 days prior to registration

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Mayo Clinic	Rochester	Minnesota	United States	55905
3	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Robert Miller, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01880528
• Other Study ID Numbers: MC1221; NCI-2013-01139; 12-008062; P30CA015083
• First Posted: Jun 19, 2013
• Last Update Posted: Jan 2, 2020
• Last Verified: Dec 1, 2019

• Additional relevant MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma; Dyspnea; Lisinopril

Study Results

Participant Flow

Arm/Group Title	Arm I (Lisinopril)	Arm II (Placebo)
Arm/Group Description	Beginning within 7 days of beginning radiation therapy, patients receive lisinopril PO QD.	Beginning within 7 days of beginning radiation therapy, patients receive placebo PO QD.
Period Title: Overall Study
STARTED	12	11
COMPLETED	11	10
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Arm I (Lisinopril)	Arm II (Placebo)	Total
Arm/Group Description	Beginning within 7 days of beginning radiation therapy, patients receive lisinopril PO QD.	Beginning within 7 days of beginning radiation therapy, patients receive placebo PO QD.	Total of all reporting groups
Overall Participants	11	10	21
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62.0	62.0	62.0
Sex: Female, Male (Count of Participants)
Female	5 45.5%	3 30%	8 38.1%
Male	6 54.5%	7 70%	13 61.9%

Outcome Measures

1. Primary Outcome

Title	Incidence of Grade 3 or Higher Hypotension, Acute Kidney Injury, Allergic Reaction, or Anaphylaxis, as Measured Using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0
Description	Incidence of grade 3 or higher hypotension, acute kidney injury, allergic reaction, or anaphylaxis, as measured using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. Descriptive statistics of frequency (percentage) will be used to summarize adverse event (AE) incidence and severity in the lisinopril and placebo arms separately.
Time Frame	Up to 3 months post-radiation therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Lisinopril)	Arm II (Placebo)
Arm/Group Description	Beginning within 7 days of beginning radiation therapy, patients receive lisinopril PO QD.	Beginning within 7 days of beginning radiation therapy, patients receive placebo PO QD.
Measure Participants	11	10
Number [percentage of patients]	0	0

2. Secondary Outcome

Title	Acute Respiratory Distress (Dyspnea), Measured Using of the Maximum Score, at Any Time, of the Shortness of Breath Question (Item #4) on the LCSS (Worst Dyspnea Score)
Description	Acute respiratory distress (dyspnea), measured using of the maximum score, at any time, of the shortness of breath question (Item #4 "How much shortness of breath do you have?") on the Lung Cancer Symptom Scale (LCSS) (Worst Dyspnea Score). The LCSS tool contains 6 major symptoms associated with lung malignancies and their effect on overall symptomatic distress, functional activities, and global quality of life (QOL). The item scale ranges from 0-10 (0 = None; 10 = As much as it could be) where the LCSS scoring algorithm is applied to convert to a 0-100 point scale where 100 is best quality of life (QOL), for comparability. Patient scores range from 0 to 100, where 100 was best QOL (i.e. less pulmonary distress).
Time Frame	Up to 3 months post-radiation therapy

Outcome Measure Data

Analysis Population Description

Patients who completed the LCSS Item #4 at any time during the study are included in this analysis.

Arm/Group Title	Arm I (Lisinopril)	Arm II (Placebo)
Arm/Group Description	Beginning within 7 days of beginning radiation therapy, patients receive lisinopril PO QD.	Beginning within 7 days of beginning radiation therapy, patients receive placebo PO QD.
Measure Participants	12	10
Mean (Standard Deviation) [score on a scale]	77.5 (23.8)	42.0 (27.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Lisinopril), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Kruskal-Wallis
	Comments

3. Secondary Outcome

Title	Experience Shortness of Breath During Exercise as Measured Using Item #3 on the Symptom Experience Questionnaire (SEQ) at Week 4
Description	Experience shortness of breath during exercise as measured using Item #3 ("Over the past week, did you experience shortness of breath when you exercise or exert yourself?") on the Symptom Experience Questionnaire (SEQ) at Baseline. The item scale ranges from 0-10 (0 = Not at all; 10 = As bad as it can be) where the SEQ scoring algorithm is applied to convert to a 0-100 point scale where 100 is best quality of life (QOL), for comparability.
Time Frame	At Week 4

Outcome Measure Data

Analysis Population Description

Patients who completed Item #3 on the SEQ at week 4 are included in this analysis.

Arm/Group Title	Arm I (Lisinopril)	Arm II (Placebo)
Arm/Group Description	Beginning within 7 days of beginning radiation therapy, patients receive lisinopril PO QD.	Beginning within 7 days of beginning radiation therapy, patients receive placebo PO QD.
Measure Participants	3	7
Mean (Standard Deviation) [score on a scale]	100 (0)	68.6 (27.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Lisinopril), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0337
	Comments
	Method	Kruskal-Wallis
	Comments

4. Secondary Outcome

Title	Quality of Life (Dyspnea When Climbing Stairs) Assessed Using Item #5 of the European Organization for Research on the Treatment of Cancer Lung Cancer Module Survey (EORTC-QLQ-LC13) at Week 4
Description	Dyspnea when climbing as measured using item #5 ("Were you short of breath when you climbed stairs?") of the EORTC-QLQ-LC13 at Week 4. The item scale ranges from 1-4 (1 = Not at all; 4 = Very Much) where the EORTC-QLQ-LC13 scoring algorithm is applied to convert to a 0-100 point scale where 100 is best quality of life (QOL), for comparability.
Time Frame	At Week 4

Outcome Measure Data

Analysis Population Description

Patients who completed item #5 on the EORTC-QLQ-LC13 at week 4 are included in this analysis.

Arm/Group Title	Arm I (Lisinopril)	Arm II (Placebo)
Arm/Group Description	Beginning within 7 days of beginning radiation therapy, patients receive lisinopril PO QD.	Beginning within 7 days of beginning radiation therapy, patients receive placebo PO QD.
Measure Participants	8	9
Mean (Standard Deviation) [score on a scale]	83.3 (17.8)	51.9 (33.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Lisinopril), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0427
	Comments
	Method	Kruskal-Wallis
	Comments

5. Secondary Outcome

Title	Total LCSS Score as Measure by the Lung Cancer Symptom Scale (LCSS) at Week 4
Description	Total LCSS score as measured using the Lung Cancer Symptom Scale (LCSS) at Week 4. The item scale ranges from 0-10 (0 = None; 10 = As much as it could be) where the LCSS scoring algorithm is applied to convert to a 0-100 point scale where 100 is best quality of life (QOL), for comparability.
Time Frame	At Week 4

Outcome Measure Data

Analysis Population Description

Patients who completed the LCSS at week 4 are included in this analysis.

Arm/Group Title	Arm I (Lisinopril)	Arm II (Placebo)
Arm/Group Description	Beginning within 7 days of beginning radiation therapy, patients receive lisinopril PO QD.	Beginning within 7 days of beginning radiation therapy, patients receive placebo PO QD.
Measure Participants	8	9
Mean (Standard Deviation) [score on a scale]	83.8 (11.2)	66.5 (17.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Lisinopril), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0237
	Comments
	Method	Kruskal-Wallis
	Comments

Adverse Events

Time Frame	Up to 3 months post-radiation therapy
Adverse Event Reporting Description	Each CTCAE term is a representation of a specific event used for medical documentation & analysis & is a single MedDRA Lowest Level Term (LLT). All graded AEs are reported for patients assessed for AEs and completed AE form. Serious AE (SAE) reports may include any secondary serious or non-serious events considered related to the primary event (the reason for filing an expedited report); collectively, these events are referred to as Expedited AEs, & appear in the SAE table.
Arm/Group Title	Arm I (Lisinopril)		Arm II (Placebo)
Arm/Group Description	Beginning within 7 days of beginning radiation therapy, patients receive lisinopril PO QD.		Beginning within 7 days of beginning radiation therapy, patients receive placebo PO QD.
All Cause Mortality
	Arm I (Lisinopril)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/10 (0%)
Serious Adverse Events
	Arm I (Lisinopril)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/12 (33.3%)		1/10 (10%)
Blood and lymphatic system disorders
Anemia	1/12 (8.3%)	1	0/10 (0%)	0
Febrile neutropenia	1/12 (8.3%)	1	0/10 (0%)	0
Investigations
Neutrophil count decreased	2/12 (16.7%)	5	0/10 (0%)	0
Platelet count decreased	1/12 (8.3%)	1	0/10 (0%)	0
White blood cell decreased	2/12 (16.7%)	4	0/10 (0%)	0
Nervous system disorders
Syncope	1/12 (8.3%)	1	0/10 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/12 (8.3%)	1	0/10 (0%)	0
Dyspnea	0/12 (0%)	0	1/10 (10%)	1
Vascular disorders
Hematoma	1/12 (8.3%)	1	0/10 (0%)	0
Hypertension	1/12 (8.3%)	3	0/10 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm I (Lisinopril)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/12 (91.7%)		10/10 (100%)
Gastrointestinal disorders
Dyspepsia	1/12 (8.3%)	1	0/10 (0%)	0
Esophagitis	3/12 (25%)	4	0/10 (0%)	0
General disorders
Fatigue	1/12 (8.3%)	5	0/10 (0%)	0
Investigations
Platelet count decreased	1/12 (8.3%)	1	0/10 (0%)	0
White blood cell decreased	1/12 (8.3%)	2	0/10 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/12 (0%)	0	1/10 (10%)	1
Nervous system disorders
Presyncope	1/12 (8.3%)	1	0/10 (0%)	0
Renal and urinary disorders
Acute kidney injury	3/12 (25%)	5	0/10 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	9/12 (75%)	26	9/10 (90%)	32
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/12 (8.3%)	1	0/10 (0%)	0
Vascular disorders
Hypotension	5/12 (41.7%)	6	4/10 (40%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.