The following protocol information is provided solely to describe how the authors conducted the research underlying the published report associated with the following article: Prevention of Pegfilgrastim-Induced Bone Pain: A Phase III Double-Blind Placebo- Controlled Randomized Clinical Trial of the University of Rochester Cancer Center Clinical Community Oncology Program Research Base Kirshner, et al DOI: 10.1200/JCO.2011.37.8364 The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Information for Contributors (http://jco.ascopubs.org/site/ifc/protocol.xhtml) only specific elements of the most recent version of the protocol are requested by JCO. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of these protocol materials or due to any errors or omissions. Individuals seeking additional information about the protocol are encouraged to consult with the corresponding author directly.
UNIVERSITY OF ROCHESTER CANCER CENTER CCOP RESEARCH BASE Prevention of Pegfilgrastim-Induced Bone Pain (PIBP): A Phase III Double-Blind Placebo-Controlled Clinical Trial NCI Protocol # URCC-06-06 URCC Protocol # URCC07079 Study Chair: Study Co-Chair: Biostatistics Chair: Jeffrey J. Kirshner, MD, HOACNY CCOP Gary R. Morrow, PhD, MS, URCC Jeffrey K. Giguere, MD, Greenville CCOP Pascal Jean-Pierre, PhD, URCC Charles Heckler, PhD, URCC James P. Wilmot Cancer Center URCC CCOP Research Base 601 Elmwood Avenue, Box 704 Rochester, NY 14642 (585) 275-5513 NCI Concept Submission 19-Dec-06 Revised Concept Submission 15-Feb-07 NCI Concept Approval 24-Apr-07 Protocol Submitted to NCI/PRC 2-Aug-07 Revised Protocol Submission 19-Dec-07 Amendment #1 29-Apr-08
Study Schema N=322 Phone call 3-5 days after pegfilgrastim administration Prior to first dose of pegfilgrastim -Consent -Questionnaires -Randomize to naproxen/placebo [Baseline] Day 2, 3 or 4 of chemotherapy cycle -Pegfilgrastim administered SC -Begin study medication -Return baseline questionnaires -Outcome questionnaires Study participation ends -Complete and mail outcome questionnaires [Outcome] 5 to 8 days of naproxen 500mg or matching placebo
3.0 Objectives 3.1 Primary Objectives: 3.1.1 To determine if daily administration of naproxen, in an oral dose of 500 mg twice daily (BID) can prevent or reduce the severity and duration of PIBP compared to placebo. 3.2 Secondary Objectives: 3.2.1 To identify potential risk factors for the development of PIBP 3.2.2 To identify potential clinical predictors for the response or failure to respond to naproxen in an oral dose of 500 mg twice daily (BID) for prevention of PIBP. 3.2.3 To assess the toxicity of the administration of naproxen, in an oral dose of 500 mg twice daily (BID) in the preventive setting in this population of patients. 4.0 Participant Eligibility Study participants: 4.1 Must be diagnosed with a non-hematologic (non-myeloid) malignancy, be scheduled to receive chemotherapy and be scheduled to receive a first dose of pegfilgrastim (Neulasta ) (6 mg given sub-cutaneously [SC]) to ameliorate chemotherapy-induced neutropenia. 4.1.1 Chemotherapy may be for adjuvant, neoadjuvant, curative or palliative intent. 4.1.2 The pegfilgrastim must be administered on Day 2, 3 or 4 of the chemotherapy cycle (not more than 72 hours following chemotherapy). Date and time of pegfilgrastim administration must be recorded on the chemotherapy flow sheet. 4.2 Must not have clinical evidence of active gastrointestinal bleeding, a history of gastrointestinal bleeding, or gastric or duodenal ulcers. 4.3 Must not have undergone surgery on the heart within the past six months.
4.4 Must not have a known allergy to naproxen or have developed the triad of asthma, rhinitis, and nasal polyps after taking aspirin or other nonsteroidal antiinflammatory drugs. 4.5 Must not be currently taking any NSAID, such as aspirin and ibuprofen, any product containing naproxen (e.g. Naprosyn, EC-Naprosyn, Anaprox, Anaprox- DS, Naprosyn suspension, Aleve), or any steroid medication on a regular basis. 4.6 Must not be regularly taking any prescription or non-prescription medications for pre-existing chronic pain. 4.6.1 Patients who are on cardioprotective aspirin up to 325 mg per day are allowed. 4.7 Must not be currently taking therapeutic doses of Warfarin. 4.8 Must not have pre-chemotherapy serum creatinine level greater than 1.5 X the upper limit of normal (ULN). 4.9 Must not be pregnant or nursing. 4.9 Must be able to understand English (all assessment instruments are in English). 4.10 Must be 18 years of age or older. 4.11 Must give written informed consent. 6.0 Treatment Protocol, Study Outline This is a randomized, double-blind, placebo-controlled Phase III clinical intervention trial to assess the efficacy of naproxen vs. placebo to prevent or ameliorate bone pain induced by pegfilgrastim (PIBP). Both groups of patients will keep a diary of the doses of study medication (naproxen or placebo) as well as any other pain medications and record their experience with PIBP. Details of the study design are as follows. 6.1 Patients must be approached for study participation before they receive their first dose of pegfilgrastim. Patients who are eligible and agree to participate will sign a consent form prior to completing baseline questionnaires or undergoing any other study procedures. 6.2 Participant instructions and tasks: 6.2.1 Prior to (within two weeks of) the administration of their first dose of pegfilgrastim (baseline assessment), participants will complete baseline
questionnaires including questions concerning the presence, location and duration of any bone or joint pain as well as the manner in which the pain was treated. 6.2.2 When they receive their first dose of pegfilgrastim, (or at the chemotherapy visit if pegfilgrastim will be self-administered by the participant at home) each participant will be given a bottle containing all of their assigned study medication (16 tablets of naproxen or placebo) for up to 8 days of chemotherapy cycle one. 6.2.2.1 Participants will be instructed to take one tablet by mouth, twice daily, in the morning and in the evening, beginning on the day they receive their first dose of pegfilgrastim, and continuing for at least five days (up to a maximum of eight days). 6.2.2.2Participants will be given a total of 16 tablets of study medication so that they can take their medication for up to eight days if necessary for pain control. 6.2.2.3Participants will be instructed to take their medication with food or milk. 6.2.2.4The first dose of study medication should be taken prior to the administration of pegfilgrastim or as soon as possible after it is administered. 6.2.2.5A missed dose of study drug may be taken if the time is within four hours of when the dose is customarily taken. 6.2.2.6If the elapsed time since the missed dose is longer than four hours, that dose should not be taken and the next scheduled dose should be taken at the appropriate time. 6.2.3 Patients will be instructed to return their medication bottles at the following chemotherapy cycle. 6.2.4 At the study visit at which pegfilgrastim is administered, (or at the chemotherapy visit if pegfilgrastim will be self-administered by the participant at home) participants will be given a second set of questionnaires (outcome assessment) to complete at home and mail back to the treatment site. The set will include a questionnaire assessing any development of new bone or joint pain, its location, onset and duration, severity, and an assessment of the efficacy of the assigned medication. 6.2.5 Participants will mail the completed questionnaires back to each site in postage-paid envelopes provided.
6.2.6 A phone call will be made to participants on the third, fourth or fifth day following pegfilgrastim (Days 5, 6 or 7 of the chemotherapy cycle) to remind them to complete and mail back the questionnaires. 6.3 Treatment Duration 6.3.1 Participants take study medication for one chemotherapy treatment only, i.e., the first chemotherapy treatment where pegfilgrastim is administered. 6.3.2 The trial ends when the completed measures have been returned following the participant s first dose of pegfilgrastim. 6.4 Ancillary Treatments 6.4.1 Health care providers may prescribe acetaminophen, tramadol (Ultram ), narcotics or other analgesics except NSAIDs for participants as needed for control of pain. 6.4.2 If the use of any additional medication for bone pain becomes medically indicated, the participant may remain on the study medication and should record the name and dose of the additional pain medication as well as date(s) and time(s) they took the additional medication on the forms provided. 7.1 Primary Outcome Measure 7.0 Treatment Evaluation Our primary outcome measure will be the area under the curve for pain from baseline through day 5. (Day 1 = the day pegfilgrastim is administered.) Daily pain severity will be as recorded by the patient in the daily diary. Any rating of pain, from 1 to 10 on the scale will be considered a day with pain. This outcome measure will incorporate both the severity and the duration of the patient s bone pain. Pain measures after day 5 will be used for exploratory analysis only, to determine the proportion of patients whose pain lasts longer than 5 days. Pain duration will be measured as the number of days with pain. This information will be obtained from a daily diary given to each participant. Pain relief is also assessed in the BPI by asking patients what percent of their pain was relieved by medication, however the primary assessment about pain relief will be through the daily diary. As another way to assess the efficacy of the naproxen for pain relief, we will look at the amount of additional analgesia used by the patient, as recorded in the daily diary.
The Daily Diary is a three-page questionnaire. On each day for at least five days (and up to eight days) each participant will record the worst severity of any bone pain experienced that day ( using the worst pain question as written in the BPI), indicate the name and number of doses taken of any pain medication they took other than their assigned study medication, and will also indicate whether or not they took their study medication. 7.2 Secondary Outcome Measures Potential risk factors for the development of PIBP as well as for response or failure to respond to treatment, including participant age, sex, ethnicity, disease and stage, and chemotherapeutic regimen, will be obtained from the participant s medical record and from participant interview, and will be recorded on the On- Study form. We will also assess the presence or severity of symptoms prior to study enrollment and at study outcome using the Symptom Inventory. The Symptom Inventory was modified from measures created at MD Anderson and Memorial- Sloan Kettering Cancer Centers and is comprised of a list of 13 symptoms. The severity of each symptom is rated on an 11 point scale anchored by 0 = Not Present and 10 = As Bad As You Can Imagine. This questionnaire is used by our Clinical Trials Office in URCC investigator-initiated clinical trials. Oncologists at the URCC also use the measure in clinical practice in both Radiation and Medical Oncology clinics. Assessment of symptoms at baseline will be used to identify additional risk factors for the development of PIBP. Completion of the SI on Day 5 will be used to determine whether naproxen affects the presence or severity of symptoms other than pain (e.g. sleep, fatigue) and to identify potential adverse effects of the medication. The Brief Pain Inventory (Short Form) (BPI) will be used to measure general pain at baseline and on day 5 (or up to day 8 after pegfilgrastim administration, if the pain continues). The BPI is a self-report measure of pain intensity and the interference of pain with function. The original BPI was developed and validated by the Pain Research Group, WHO Collaborating Centre for Symptom Evaluation in Cancer Care. (6;7) Validity and reliability of the original BPI have been verified across several different cultures and languages. (7) We will use the short form of the BPI (BPI-SF). The reliability and validity of this modified, eight item, short form when used to assess pain on a daily basis has also been established. (8) It has been used extensively in clinical studies of patients with cancer. (9) In this questionnaire, pain intensity over the previous 24 hours is assessed at its worst, its least, on average and right now is assessed using an 11 point numerical rating scale anchored by 0 = No pain and 10 = Pain as bad as you can imagine. Interference of pain with general activity, mood, walking ability, normal work, interpersonal relations, sleep and enjoyment of life is assessed with an 11 point numerical rating scale anchored by 0 = Does not interfere and 10 = Completely interferes. A composite interference score will be calculated from the means of the individual responses.
We will track the occurrence and severity of toxicity from the medication using the AE reports submitted to the URCC Research Base. As stated in Section 6.0, toxicity will be assessed and reported using the NCI Common Toxicity Criteria. Patients will also record side effects from the study medication in the daily diary. 8.0 Drug Characteristics, Dosage and Administration 8.1 General Information 8.1.1 Description: naproxen is a practically odorless, white to off-white crystalline substance. It is a lipid soluble, practically insoluble in water at low ph and freely soluble in water at high ph. The chemical formula is (+)-6-methoxy- -methyl-2-naphthleneacetic acid. 8.1.2 Clinical Pharmacology: naproxen is a non-steroidal anti-inflammatory drug with analgesic and antipyretic properties. Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The elimination half-life is 12-17 hours and does not differ between products. Approximately 95% is excreted in the urine. 8.1.3 Mode of action: naproxen inhibits prostaglandin synthesis. Additional modes of action are possible, but have not been defined. 8.1.4 Pregnancy category C. There are no adequate and well-controlled studies in pregnant women. 8.2 Drug Formulation and Procurement 8.2.1 All study medications (drug and placebo) will be supplied. The study drugs will be packaged in bottles of 16 tablets of naproxen 500 mg or placebo (identical in appearance, smell and taste to the study medication) each. The bottles will be distributed to the individual CCOPs from the Research Base. 8.3 Storage and Stability 8.3.1 Naproxen is stable at normal room temperatures (between 68 F and 77 F). The study drug naproxen and the placebo must be stored at room temperature, in a dry place and in a securely locked, substantially constructed cabinet or enclosure. 8.4 Dosage and Administration
8.4.1 Prescription-strength naproxen and placebo will be administered in the dosage and manner specified for each arm in section 5.5. 8.5 Adverse Effects 8.5.1 Adverse effects occurring in more than 3% - 9% of 960 patients treated for rheumatoid arthritis or osteoarthritis include constipation, heartburn, abdominal pain, nausea, headache, dizziness, drowsiness, itching, skin eruptions, ecchymoses, tinnitus, edema and dyspnea. Minor gastrointestinal problems such as dyspepsia are common and may develop early in the course of treatment. Serious gastrointestinal toxicity such as bleeding, ulceration and perforation have been reported in approximately 1% of individuals taking NSAIDs for 3-6 months, and in 2%-4% of patients taking these medications for one year, much longer periods than the time over which the drug will be administered in this study. In post-marketing studies of naproxen, photosensitivity reactions and changes in blood pressure (hypotension or hypotension) were observed in less than 1% of patients. 8.5.1.1 Patients will be instructed to watch for signs of gastrointestinal bleeding (blood in vomit or bloody, black, or tarry stools). 8.5.1.2 Patients will be instructed to stop taking the study medication and call their treating oncologist immediately if any sign of gastrointestinal bleeding occurs. 8.5.2 Patients will be instructed to avoid drinking alcoholic beverages while taking the study medication. 8.5.3 Since drowsiness and dizziness may occur, patients will be urged to use care when driving or operating heavy equipment while taking the study drug. 8.5.4 Precautions Potential Drug Interactions. 8.5.4.1 Caution should be used in patients receiving methotrexate. These patients should be monitored for evidence of greater-thananticipated methotrexate-related hematologic and gastrointestinal toxicity. 8.5.4.2 Caution should be used in patients receiving ACE-inhibitors, as concomitant administration of naproxen may decrease the antihypertensive effect of these drugs.
8.5.4.3 Caution should be used in patients receiving lithium. These patients should be monitored for signs of lithium toxicity. (Diarrhea, vomiting, drowsiness, muscular weakness, and lack of coordination are early signs of lithium toxicity, whereas giddiness, ataxia, blurred vision, tinnitus or a large output of dilute urine may be seen at serum levels of lithium higher than 2 meq/l.) 8.5.4.4 Caution should be used in patients receiving furosemide (Lasix) and thiazides as naproxen may decrease the natriuretic effect of these drugs in some patients. 9.0 Statistical Considerations 9.1 The assumptions underlying all statistical analyses will be thoroughly checked using appropriate graphical and numerical methods. (10;11) In the case of serious violations of the assumptions, appropriate nonparametric methods will be attempted. If outliers or influential data are detected, the accuracy of the data will be investigated. If no errors are found, analyses may be repeated after removing these cases to evaluate their impact on the results, however, the final analyses will include these data points. All statistical tests will be performed at the two-tailed 5% level of significance. Likewise, 95% confidence intervals will be constructed for estimation of effects (e.g., difference in mean change scores of pain severity between the treatment group and the placebo group). 9.2 Data will be analyzed on an "intent-to-treat" basis; participant data will be included in the treatment group to which the participant was randomized regardless of any subsequent changes to the treatment. 9.3. Every effort will be made to encourage and facilitate participants completion of questionnaires. In the event of missing data, the reasons for missing data will be recorded and tabulated according to treatment groups. 9.4 Statistical Analysis 9.4.1 Baseline demographic and medical history variables will be summarized for each treatment group. Summaries for quantitative variables, such as age, will include the mean, median, standard deviation, minimum, and maximum. For qualitative variables, such as gender, summaries will include the number and percent of patients for each outcome. Treatment group comparisons will be based on either the two-sample t-tests for quantitative variables or chi-square tests for qualitative variables.
9.4.2 The primary outcome measure for this study is the area under the curve (AUC) for the patient s pain score from baseline through day five following pegfilgrastim administration. The AUC measure is the pain scores reported on the daily diary for the five days of observation. The X axis of the AUC represents duration of pain (5 days) and the Y axis represents severity (daily pain score.) This will be compared between the two treatment groups using the Analysis of Covariance (ANCOVA) method adjusting for baseline pain measures. 9.4.3 Additional analysis will address the secondary objectives of determining if there are any characteristics (age, sex, disease, type of chemotherapy regimen, et al.) that predict failure to prevent pain and if there are characteristics that correlate with the development and/or severity of pain. These will be analyzed using linear regression for the AUC of pain and the logisticregression for development of the pain. Baseline characteristics, treatment group and the interaction between baseline characteristics and treatment will be included as the covariates. 9.4.4 Differences in the proportion of patients developing serious toxicities in the two groups will be analyzed using chi-square tests. 9.4.5 There is no interim analysis planned. 9.5 Sample Size 9.5.1 From preliminary data from the Syracuse CCOP (HOACNY), we collected data on the pain severity score at the start of the pain, the pain score on the last day of the pain and the duration of the pain. From these data we were able to calculate the area under the curve for the pain score assuming the pain score changed linearly over this period. The average AUC is 5.02 and the standard deviation is 7.64. In order to have 80% power to detect a difference of 2.51 (a 50% reduction of the pain in the treatment group as compared to the control group) for the two treatment groups, using a twosided test with significance level of 0.05, we would need 145 evaluable people in each treatment group, thus 290 evaluable patients in total. Anticipating a 10% dropout rate, we will accrue approximately 322 patients, 161 in each group. 9.6 Representation of Women and Minorities. 9.6.1 None of the eligibility criteria for the study involve gender or ethnicity. However, the majority of participants may comprise women with breast cancer who are frequent recipients of chemotherapy. The Minority Based CCOP members affiliated with our group have expressed interest in participating in this protocol. Past enrollment in our CCOP studies has closely paralleled the gender and ethnic composition of the available population.
9.6.2 Careful review of the literature gives no reason to suspect differences in either outcome measures effects by gender or ethnicity. Subgroup analyses of study data will be conducted to check for such differences. The methods of analysis will follow those of the primary analysis, but power will be lower due to smaller sample sizes within subgroups.