Methylphenidate in Treating Patients With Fatigue Caused by Cancer

Study Overview
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Brief Summary
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RATIONALE: Methylphenidate may help relieve fatigue caused by cancer. It is not yet known whether methylphenidate is more effective than a placebo in relieving fatigue and improving quality of life in patients with cancer. PURPOSE: This randomized phase III trial is studying methylphenidate to see how well it works in treating patients with fatigue caused by cancer.

Detailed Description
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OBJECTIVES: Primary Test the efficacy of long-acting methylphenidate in patients with cancer-related fatigue as measured using an item of the Brief Fatigue Inventory. Secondary Evaluate the tolerability and adverse events associated with this drug in these patients. Study the effect of this drug on quality of life (QOL)-related variables (vitality, sleep quality, overall QOL, QOL domains, other fatigue measures, and perceived treatment efficacy) in these patients. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to disease stage (0, I, or II vs III or IV), level of fatigue at baseline (4-7 vs 8-10), concurrent biological therapy (yes vs no), concurrent chemotherapy (yes vs no), and concurrent radiotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral methylphenidate daily on days 1-28. Arm II: Patients receive oral placebo daily on days 1-28. Patients in both arms complete questionnaires to assess their symptoms of fatigue, overall mood, quality of life, sleep quality, and adverse effects from treatment at baseline and once weekly for 4 weeks. Patients also complete a Symptom Experience Diary. McNeil Consumer & Specialty Pharmaceuticals provided medication support for NCCTG N05C7. PROJECTED ACCRUAL: A total of 140 patients will be accrued for this study.

Official Title
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Long Acting Methylphenidate (Concerta™) for Cancer-Related Fatigue: A Phase III, Randomized, Double-Blind Placebo Controlled Study

Conditions
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Fatigue, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: methylphenidate hydrochloride
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years of age Men or women with a history of cancer-related fatigue as defined by a score ≥ 4 on a fatigue numerical analogue scale (0 - 10) Fatigue for ≥ 1 month prior to registration ECOG Performance Score (PS) 0, 1, or 2 Life expectancy ≥ 6 months Histologic or cytologic proven cancer other than brain cancer or CNS lymphoma Laboratory values obtained ≤ 30 days prior to registration: Hgb ≥ 10 g/dL Willing and able to provide informed consent Negative pregnancy test (urine or serum) done ≤ 7 days prior to registration, for women of childbearing potential only Ability to complete questionnaire(s) by themselves or with assistance Biological therapy (i.e. immunotherapy, biotherapy), chemotherapy or radiation therapy will be allowed Use of a stable dose of anti-depressants (except tricyclic anti-depressants) will be allowed Erythropoietic agents to treat anemia, and steroids as a part of cancer treatment and for symptom management (except for fatigue) will be allowed Exclusion Criteria: Hypersensitivity to methylphenidate Any prior use of methylphenidate Concomitant (≤ 2 weeks) use of prescription stimulants (pemoline, modafinil, amphetamines); other medications, herbal products or dietary supplements for fatigue Uncontrolled hypertension [defined as systolic blood pressure (BP) ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg on 2 separate visits ≤ 2 months prior to randomization]; or a resting heart rate > 100 Moderate or severe pain as defined by an average daily score ≥ 4 on a pain analog scale (0 - 10) Known brain metastasis or primary CNS malignancy Clinically significant acute or chronic progressive or unstable neurologic (dementia, delirium, or seizure disorder), hepatic, renal, cardiovascular, thyroid, or respiratory disease that would limit participation in the study per MD discretion or judgment Psychiatric disorder such as manic depression, anxiety disorder, bipolar disorder, obsessive compulsive disorder, or schizophrenia Major surgery < 4 weeks prior to registration. (Note: Insertion of central venous catheter is not considered major surgery.) Using a drug contraindicated when taken concurrently with methylphenidate: coumarin anticoagulants, anticonvulsants, tricyclic antidepressants, antipsychotics, monoamine oxidase inhibitors, clonidine, theophylline, and pseudoephedrine Note: use of Compazine prescribed as an antiemetic is permitted for use while participating in this study. Additional medical conditions where use of methylphenidate is contraindicated: glaucoma, motor tics, family history or diagnosis of Tourette's syndrome, history of drug or alcohol abuse or intestinal obstruction. Pregnant women or nursing women. Women of childbearing potential who are unwilling to employ adequate contraception. This study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown. Untreated hypothyroidism (TSH ≥ 5)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral methylphenidate hydrochloride daily on days 1-28. | Drug: methylphenidate hydrochloride<br>* Given orally<br>|
| Placebo Comparator: Arm II<br>Patients receive oral placebo daily on days 1-28. | Other: placebo<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prorated AUC of Total Fatigue as Measured by the Brief Fatigue Inventory (BFI) at Baseline and at Weeks 1-4 | The prorated area under the curve (AUC) for the usual fatigue question of the BFI at baseline and at weeks 1-4 after being translated onto a 0 (poor quality of life (QOL) or bad symptoms) to 100 (best QOL or no symptoms) point scale was calculated as the following: For those completed 4 weeks item: AUC/4; For those completed up to week 3 item: (AUC * 4) / 3; For those completed up to week 2 item: AUC * 2; For those completed up to week 1 item: AUC * 4; The prorated AUC scores were then transformed onto 0 to 100 point scale with 0 (poor QOL or bad symptoms) and 100 (best QOL or no symptoms) for analysis. | Baseline to week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of Adverse Events as Measured by the Symptom Experience Diary Based on Mean Changes From Baseline to Week 4 | The Symptom Experience Diary (SED) consists of 12 items. All scores were translated onto a 0-100 point scale, with 0 represent poor quality of life (QOL) or bad symptom and 100 is best QOL or no symptoms.The change in severity of adverse events was calculated as subtracting the item scores at baseline from the scores at week 4. | Baseline and Week 4 | 
| AUC of Sleep Quality as Measured by the Pittsburgh Sleep Quality Index at Baseline and at Weeks 1-4 | Pittsburgh Sleep Quality Index (PSQI) consists of 19 items and 7 scales. The AUC for the overall PSQI at baseline and at weeks 1-4 after being translated onto a 0 to 100 point scale was calculated. Higher scores are better. | Baseline to Week 4 | 
| AUC of Vitality as Measured by the Short Form-36 Vitality Subscale at Baseline and at Weeks 1-4 | The SF-36 is a 36-item short form to measure health status in various populations. The vitality subscale is comprised of 4 items and is a measure of energy level as well as fatigue. The AUC for the vitality subscale at baseline and at weeks 1-4 after being translated onto a 0 to 100 point scale was calculated. Higher scores are better. | Baseline to Week 4 | 
| AUC of Overall Quality of Life (QOL) and QOL Domains as Measured by the Linear Analogue Self Assessment at Baseline and at Weeks 1-4 | Linear Analogue Self Assessment (LASA) consists of 6 single-item numeric analogue scales. The AUC for the six-items at baseline and at weeks 1-4 after being translated onto a 0 to 100 point scale was calculated. Higher scores are better. | Baseline to Week 4 | 
| AUC of Other Fatigue Scores as Measured by Items of the Brief Fatigue Inventory (BFI) at Baseline and at Weeks 1-4 | Area under the curve (AUC) for the other fatigue items of the BFI at baseline and at weeks 1-4 after being translated onto a 0 to 100 point scale was calculated. Higher scores are better. | Baseline to Week 4 | 
| Anchor-based Minimally Important Difference in SGIC Overall Quality of Life Based on Mean Changes From Baseline to Week 4 on BFI Usual Fatigue | Perceived treatment efficacy was measured by the Subject Global Impression of Change (SGIC). The SGIC is a 3-point item in which the patient rates the change in the overall status since beginning the study drug (ranging from very much better, moderately better, a little better, about the same, a little worse, moderately worse, to very much worse). The average change in patient fatigue scores for those participants who express a perceived change of a little better via the SGIC scores were calculated. BFI usual fatigue item score was translated into 0 to 100 point scale for the analysis, with 0 (poor QOL or bad symptoms) and 100 (best QOL or no symptoms). | Baseline and Week 4 | 
| Anchor-based Minimally Important Difference in SGIC Physical Condition Based on Mean Changes From Baseline to Week 4 on BFI Usual Fatigue | Perceived treatment efficacy was measured by the Subject Global Impression of Change (SGIC). The SGIC is a 3-point item in which the patient rates the change in the overall status since beginning the study drug (ranging from very much better, moderately better, a little better, about the same, a little worse, moderately worse, to very much worse). The average change in patient fatigue scores for those participants who express a perceived change of a little better via the SGIC scores were calculated. BFI usual fatigue item score was translated into 0 to 100 point scale for the analysis, with 0 (poor QOL or bad symptoms) and 100 (best QOL or no symptoms). | Baseline and Week 4 | 
| Anchor-based Minimally Important Difference in SGIC Emotional State Based on Mean Changes From Baseline to Week 4 on BFI Usual Fatigue | Perceived treatment efficacy was measured by the Subject Global Impression of Change (SGIC). The SGIC is a 3-point item in which the patient rates the change in the overall status since beginning the study drug (ranging from very much better, moderately better, a little better, about the same, a little worse, moderately worse, to very much worse). The average change in patient fatigue scores for those participants who express a perceived change of a little better via the SGIC scores were calculated. BFI usual fatigue item score was translated into 0 to 100 point scale for the analysis, with 0 (poor QOL or bad symptoms) and 100 (best QOL or no symptoms). | Baseline and Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fatigue, unspecified adult solid tumor, protocol specific