Low-Dose Ibuprofen in Improving Cognitive Impairment in Patients With Non-metastatic Colorectal Cancer Receiving Chemotherapy

• ClinicalTrials.gov Identifier: NCT03186638
• Recruitment Status: Recruiting
• First Posted: June 14, 2017
• Last Update Posted: April 29, 2019
• Sponsor: Gary Morrow
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Gary Morrow, University of Rochester NCORP Research Base

Study Description

Brief Summary:

This randomized phase II trial studies how well low-dose ibuprofen in improving cognitive impairment in patients with colorectal cancer that has not spread to other places in the body who are receiving chemotherapy. Anti-inflammatory agents, such as ibuprofen, may slow the decline of cognitive processes and diseases involving the brain.

Condition or disease	Intervention/treatment	Phase
Caregiver; Cognitive Impairment; Stage 0 Colorectal Cancer AJCC v6 and v7; Stage I Colorectal Cancer AJCC v6 and v7; Stage II Colorectal Cancer AJCC v7; Stage IIA Colorectal Cancer AJCC v7; Stage IIB Colorectal Cancer AJCC v7; Stage IIC Colorectal Cancer AJCC v7; Stage III Colorectal Cancer AJCC v7; Stage IIIA Colorectal Cancer AJCC v7; Stage IIIB Colorectal Cancer AJCC v7; Stage IIIC Colorectal Cancer AJCC v7	Drug: Ibuprofen; Other: Placebo; Other: Questionnaire Administration	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To provide preliminary data on the effect of ibuprofen on alleviating chemotherapy-related cognitive impairment (CRCI) in colorectal cancer patients receiving chemotherapy compared to a placebo control, as assessed by the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog).

SECONDARY OBJECTIVES:

I. To provide preliminary data on the effect of ibuprofen on alleviating CRCI in colorectal cancer patients receiving chemotherapy compared to a placebo control by objective assessments of cognitive function.

II. To provide preliminary data on the effect of ibuprofen on alleviating CRCI in colorectal cancer patients receiving chemotherapy compared to a placebo control on phone-based cognitive function measures (digit span, word recall, digits backward, CALVT, category fluency; all from Brief Test of Adult Cognition by Telephone [BTACT]).

III. To provide preliminary data on the effect of ibuprofen on alleviating CRCI in colorectal cancer patients receiving chemotherapy compared to a placebo control on serum pro-inflammatory (MCP-1, IL-6, IL-8, TNF-alpha, sTNFR2, sTNFR1, IL-1beta) and anti-inflammatory (sIL-1Ra, IL-10) cytokines/receptors in colorectal cancer patients receiving chemotherapy.

IV. To provide preliminary data on the mediating effects of cytokine/receptor concentrations on the CRCI changes due to ibuprofen in colorectal cancer patients receiving chemotherapy compared to placebo control.

OUTLINE: Patients are randomized into 1 of 2 arms.

ARM I: Patients receive ibuprofen orally (PO) twice daily (BID) for 6 weeks.

ARM II: Patients receive placebo PO BID for 6 weeks.

After completion of study, patients are followed up periodically.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 86 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Supportive Care
• Official Title: Phase II Study of Low-Dose Ibuprofen for Cognitive Impairment in Colorectal Cancer Patients Receiving Chemotherapy
• Actual Study Start Date: May 26, 2017
• Estimated Primary Completion Date: December 1, 2020
• Estimated Study Completion Date: March 15, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (ibuprofen); Patients receive ibuprofen PO BID for 6 weeks.	Drug: Ibuprofen; Given PO; Other Names: (.+ -.)-p-Isobutylhydratropic acid; Advil; Motrin; p-Isobutylhydratropic acid; Other: Questionnaire Administration; Ancillary studies
Placebo Comparator: Arm II (placebo); Patients receive placebo PO BID for 6 weeks.	Other: Placebo; Given PO; Other Names: placebo therapy; PLCB; sham therapy; Other: Questionnaire Administration; Ancillary studies

Outcome Measures

Primary Outcome Measures :

1. Effects of ibuprofen on alleviating chemotherapy-related cognitive impairment [ Time Frame: Up to 41 days post-intervention ]
   Will be assessed by the Functional Assessment of Cancer Therapy-Cognitive Function. Means, standard deviations, and 95% confidence intervals will be determined in order to estimate preliminary population variances and effect sizes. These statistical measures will be calculated by group for the Pre and Post measures of the Functional Assessment of Cancer Therapy-Cognitive Function scores as well as the change (post-pre) in the scores using the subjects that completed the study (complete case estimation). The complete case estimates will be compared to multiple imputation estimates based on all subjects that completed pre-intervention. An analysis of covariance will be run using Functional Assessment of Cancer Therapy-Cognitive Function post-intervention as the response. Higher scores indicate better function; range is 0 to 148.

Secondary Outcome Measures :

1. Objective assessments of cognitive functions [ Time Frame: Up to 41 days post intervention ]
   Will be measured by validated neuropsychological assessment of verbal memory, attention, and executive function and paper-based measures respectively.
2. Phone-based cognitive function [ Time Frame: Up to 41 days post intervention ]
   Analysis of covariance will be used as with the primary aim analyses to assess mean differences between cognitive function assessed by the remaining objective total scores at post-intervention.
3. Pro and anti-inflammatory cytokines/receptors analysis [ Time Frame: Up to 41 days post intervention ]
   Will assess the effects of the interventions on cytokines, hypothesizing that each intervention will reduce pro-inflammatory cytokines and increase anti-inflammatory cytokines using the same analysis or covariance analysis.
4. Cytokine concentrations [ Time Frame: Up to 41 days post intervention ]
   Will provide preliminary data on the mediating effects of cytokine concentrations on the chemotherapy-related cognitive impairment changes due to ibuprofen in colorectal cancer patients receiving chemotherapy compared to placebo controls on cytokines/receptors. Will use path modeling to estimate indirect (mediation) effects, and bootstrapping to estimate the 95% confidence intervals. Will evaluate whether cytokines mediate the effect of the intervention on cognitive scores. Will involve a separate analysis for each cytokine, using linear models with arm, pre-intervention cognitive score and with/without cytokine post-pre change scores as model predictors. Will attempt to do a structural equation model where the mediator is a latent variable measured by changes in all the cytokines, and the response is a latent variable.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Have a primary diagnosis of non-metastatic colorectal cancer and have had surgery and are now receiving adjuvant or neoadjuvant chemotherapy; chemotherapy with concurrent radiation therapy (RT) is allowed

• Report any level of cognitive difficulty to the question, ?Have you noticed any cognitive problems (such as in your memory, attention, concentration, multi-tasking) since your cancer diagnosis?? any time after initiation of chemotherapy cycle 1; participant must answer YES to this question; discussion about cognitive changes can occur with the participant and a caregiver; caregiver must be at least 21 years of age

  • NOTE: If a participant answers NO, you may re-approach them at a subsequent cycle
• Be scheduled to receive oral or intravenous (IV) chemotherapy treatments over the next six weeks during the study intervention period; therapeutic clinical trial participants are allowed
• Agree not to take a daily dosage of a non-steroidal anti-inflammatory drugs (NSAID) except 81 mg aspirin for the 6-week intervention period; (higher doses of an NSAID on an ?as needed? basis for acute pain management are permitted but should not exceed more than 1000 mg on any given day)
• Have the approval of their treating physician to receive the 6 week ibuprofen/placebo regimen (200 mg twice a day and doses 8 hours apart); (physician must sign eligibility checklist prior to registration)
• Be able to swallow medication
• Be able to read English
• Not be pregnant or become pregnant during the study if the participant is a woman of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile); documentation of pregnancy can be taken from the medical record
• Have the ability to understand and to give written informed consent as assessed by the participant?s primary care physician or medical oncologist

Exclusion Criteria:

• Have confirmed metastatic disease
• Be diagnosed with a neurodegenerative disease
• Have a history of peptic ulcer disease within the last 12 months unless adequately treated as assessed by the participant?s primary care physician or medical oncologist
• Have a contraindication to NSAIDs at the oncologist?s discretion (i.e., allergy, worsening of ongoing medical problem due to NSAID, low platelet count from chemotherapy, and uncontrolled condition such as hypertension or asthma)
• Have been hospitalized for treatment of a major psychiatric illness within the last five years
• Have a serum creatinine above 1.5 upper limit of normal (ULN) (collected within the past 4 weeks); ULN is per institutional definition
• Concurrent administration of warfarin, full dose aspirin, clopidogrel, apixaban or other medications known to increase the risk of bleeding or to interfere with antiplatelet activities
• Be colorblind
• Diagnosed alcoholism within the last 5 years

Contacts and Locations

  Show 282 Study Locations

Sponsors and Collaborators

Gary Morrow

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Michelle C Janelsins; University of Rochester NCORP Research Base

More Information

• Responsible Party: Gary Morrow, Co-Director, URCC NCORP Research Base, University of Rochester NCORP Research Base
• ClinicalTrials.gov Identifier: NCT03186638 History of Changes
• Other Study ID Numbers: URCC16092; NCI-2017-00790 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); URCC16092 ( Other Identifier: University of Rochester NCORP Research Base ); URCC-16092 ( Other Identifier: DCP ); URCC-16092 ( Other Identifier: CTEP ); R21CA187500 ( U.S. NIH Grant/Contract ); UG1CA189961 ( U.S. NIH Grant/Contract )
• First Posted: June 14, 2017
• Last Update Posted: April 29, 2019
• Last Verified: April 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Colorectal Neoplasms; Cognitive Dysfunction; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Ibuprofen; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action