Pyridoxine Protocol Version 6, 8 August 2011 · 21 Dr Tham Chee Kian Dr Wong Nan Soon 22 Dr Ooi Wei...

Pyridoxine Protocol Version 6, 8 August 2011

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1 STUDY PROTOCOL 2

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RANDOMISED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL OF 5 PYRIDOXINE FOR PREVENTION OF CAPECITABINE INDUCED 6

HAND-FOOT SYNDROME 7 8

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12 Principal Investigator (PI) – National Cancer Centre 13 Dr Yap Yoon Sim 14 E-mail: [email protected] 15 16 Co-Investigators Dr Koo Wen Hsin Dr Tan Eng Huat 17 Dr Toh Han Chong Dr Darren Lim Wan Teck 18 Dr Simon Ong Dr Joanne Ngeow 19

Dr Wong Zee Wan Dr Chau Noan Minh 20 Dr Tham Chee Kian Dr Wong Nan Soon 21 Dr Ooi Wei Seong Dr John Chia 22 Dr David Tai Dr Ang Mei Kim 23 Dr Tan Min Han Dr Iain Tan Bee Huat 24 Dr Choo Su Pin Dr Lo Soo Kien 25

Dr Raymond Ng Chee Hui Dr Mabel Wong 26 Dr Miriam Tao Dr Lim Hwee Yong 27

Dr Kevin KW Tay Dr Chay Wen Yee 28 Dr Ravindran Kanesvaran Dr Lynette Ngo Su-Mien 29 Dr Ong Sin Jen Dr Tiffany Pooi Ling Tang 30 31 32 33 Address for correspondence: 34 Dr Yap Yoon Sim 35 Department of Medical Oncology 36 National Cancer Centre 37 11 Hospital Drive, 38 Singapore 169610 39 Tel: 65-64368000 40 65-96615086 41 Fax: 65-62272759 42 43 Study statistician: Mr. Wallace Chen 44 Study coordinator: Michellore Dannug/Kathyleen David 45 Research scientist: Dr. Richie Soong 46

(Oncology Research Institute, National University of Singapore) 47 48

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TABLE OF CONTENTS 50 51 Page 52

1. Study Synopsis 3 53 2. Study Aim and Objectives 4 54 3. Background and Study Rationale 4 55 4. Patient Selection 6 56

4.1 Inclusion criteria 6 57 4.2 Exclusion criteria 6 58 5. Study Design 7 59

Treatment Plan 7 60 Study Duration 7 61

6. Outcomes and measures 8 62 7. Study Procedures 8 63 8. Interventions 8 64

Management of Grade ≥2 HFS 8 65 Management of Grade 1 HFS 9 66 Chemotherapy dose modification or interruption for 67 other toxicities 9 68 8.4 Withdrawal criteria 9 69

9. Study Calendar 10 70 10. Genotyping and folate, vitamin B12 levels 10 71 11. Statistical Considerations and Randomisation 11 72

11.1 Randomisation 11 73 11.2 Sample size calculation 11 74 11.3 Statistical analysis 11 75

12. Adverse Events and Protocol Violation Policies 12 76 13. Agent Formulation, Interactions, Storage and Accountability 12 77 14. Logistical Considerations 13 78 15. Administrative aspects 13 79 16. Ethical considerations 14 80 17. Publication Policy 15 81 18. Indemnity 15 82 19. References 16 83 20. Appendices 84

20.1 ECOG performance status grading 18 85 20.2 Pyridoxine product information 19 86 20.3 Adverse events report form 23 87 20.4 Patient information sheet and informed consent form 24 88 20.6 Capecitabine dose calculation 31 89 20.7 EuroQOL (EQ-5D) questionnaire 32 90

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1. STUDY SYNOPSIS 92 93

Background 94 Capecitabine chemotherapy is frequently used in the management of colorectal and breast 95 cancers, and hand-foot syndrome (HFS) is a common side-effect. When grade 2 or greater 96 toxicity occurs, dose interruption or reduction is necessary. Pyridoxine(vitamin B6) is often 97 used to treat HFS, but the evidence is limited to retrospective observational studies. The role 98 of pyridoxine in primary prophylaxis of HFS has not been investigated. 99 100 Hypothesis 101 Concomitant pyridoxine with capecitabine reduces the risk of grade ≥2 HFS. 102 103 Objectives 104 The primary objective is to evaluate the incidence of grade ≥2 HFS in patients receiving 105 pyridoxine compared to placebo. 106 The secondary objectives are to compare the time to onset of grade ≥2 HFS (in days) and 107 impact on quality of life (QOL) in the two groups. Exploratory analyses of serum and red cell 108 folate, serum vitamin B12 and gene polymorphisms involved in capecitabine and pyridoxine 109 metabolism will be performed. 110 111 Study design 112 This is a double-blind placebo-controlled study. Patients on capecitabine single-agent 113 chemotherapy(at a dose of at least 1000mg/m2 twice daily for 14 days every 3 weeks) will be 114 randomized to receive concomitant pyridoxine or placebo daily for a maximum of 8 cycles of 115 capecitabine. Patients will be stratified according to gender and use in adjuvant/neoadjuvant 116 versus palliative setting. A total of 296 patients (148 per arm) will be enrolled over a period 117 of at least 2 years. 118 Patients who develop grade ≥2 HFS will be withdrawn from the study. Institution of daily 119 pyridoxine with or without dose reduction of capecitabine may subsequently occur at the 120 clinician’s discretion. 121 122 Study significance 123 If pyridoxine is proven to be effective in preventing HFS, there will be less dose disruption 124 and reduction, and the efficacy of the treatment may be maintained. Patient’s quality of life 125 will also improve. If the findings from the study are negative, this may lead to a change in 126 clinical practice worldwide and result in cost savings. 127 128

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2. STUDY AIM AND OBJECTIVES 130 131 The aim of the study is to determine if concomitant pyridoxine will prevent Grade 2 or 132 greater severity hand-foot syndrome (HFS) in patients receiving capecitabine. 133 134 Primary objective 135 To evaluate the incidence of grade ≥2 HFS in patients receiving concomitant pyridoxine 136 compared to placebo. 137 138 Secondary objectives 139

1. To determine the time to onset of grade ≥2 HFS 140 2. To evaluate the quality of life (QOL) changes using EuroQOL (EQ-5D) 141

questionnaires. 142 3. To study gene polymorphisms of putative relevance to capecitabine and pyridoxine 143

metabolic pathways (especially thymidylate synthase, thymidine phosphorylase, 144 dihydropyrimidine dehydrogenase, cytidine deaminase, carboxylesterase, 145 methyltetrahydrofolate reductase) and correlate serum and red cell folate levels, 146 serum vitamin B12 levels with toxicity. 147

148 149 3. BACKGROUND AND STUDY RATIONALE 150

151 Study hypothesis 152 153 Upfront pyridoxine with commencement of capecitabine reduces the risk of developing grade 154 2 or greater HFS. 155 156 Background 157 158 Colorectal cancer and breast cancer are two of the commonest types of cancer worldwide.1 In 159 Singapore, colorectal cancer (CRC) is the second commonest cancer among males with an 160 age-standardised rate (ASR) of 40.1 per 100,000 and the second commonest among Chinese 161 women with an ASR of 29.4 per 100,000.2 Breast cancer is the commonest cancer among 162 women in Singapore, with an ASR of 54.9 per 100,000.2 Capecitabine (Xeloda), an oral 163 fluoropyrimidine that is converted to 5-fluorouracil (5-FU) by an enzymatic process, has 164 shown efficacy in the treatment of both breast and gastrointestinal cancers. 165 166 As first-line therapy for metastatic colorectal cancer, two large phase III trials have shown 167 that capecitabine achieves a superior response rate (RR) and at least equivalent time to 168 disease progression (TTP) and overall survival compared with intravenous (iv) 5-169 FU/leucovorin (LV).3 In the adjuvant treatment of colon carcinoma, capecitabine has been 170 shown to be equally effective as bolus 5-FU/LV with less myelosupression and mucositis.4 171 Capecitabine is also being used in combination with irinotecan and oxaliplatin in the 172 metastatic setting.5, 6, 7 173 174 With respect to metastatic or advanced breast cancer, capecitabine is active as first-line 175 therapy and in pre-treated patients, both as monotherapy and in combination with other 176 drugs. 8, 9, 10 177 178



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As the oral route of administration also offers more convenience and patient acceptability 179 compared with iv 5-FU11, 12, capecitabine is rapidly replacing the role of iv 5-FU. 180 181 Rationale for the study 182 183 Although capecitabine has a favourable safety profile with significantly less diarrhoea, 184 stomatitis, nausea, alopecia and grade 3 or 4 neutropaenia compared to 5-FU/LV,4,13 hand-185 foot syndrome (HFS) is a common complication. The overall incidence of HFS is estimated 186 to be between 53% to 62%, with severe cases (≥Grade 3) in 16% to 18% of patients at a dose 187 of 1250mg/m2 twice daily for every 14 out of 21 days.4, 14 Although it is not a life-threatening 188 complication, it can be disabling in severe cases and affects the treatment course due to the 189 need for dose interruption or reduction once grade 2 or greater HFS occurs. With 190 capecitabine monotherapy, grade 2 or greater HFS occurs in at least two-thirds of patients 191 who develop HFS.8, 15, 16 There is less data on the incidence of HFS with capecitabine and 192 oxaliplatin combination therapy, but phase two studies suggest similar or slightly lower 193 incidence of HFS with the slightly lower dose of capecitabine. 5, 6 194 195 The specific pathophysiologic mechanism of HFS is unclear. The clinical features of HFS are 196 characteristic and evolve in stages. Most patients have their first (92.9%) or most severe 197 (67.9%) episode of HFS within the first two cycles of treatment.15 198 199 Initially, symptoms are very mild with no obvious changes to the hands and feet. Patients 200 may experience a prodrome of about 3 to 5 days, which consists of vague paraesthesias and 201 tingling of the extremities, or painless swelling or erythema (grade 1). If the drug is 202 continued, the syndrome progresses with painful erythema and swelling (grade 2). It may 203 further progress to fissuring, ulceration and desquamation involving the hands and feet, 204 leading to extreme pain when grasping objects or walking (grade 3). 15 Resolution of HFS 205 occurs upon discontinuation of capecitabine. Histologically, the condition is marked by 206 hyperkeratosis associated with an inflammatory cell infiltrate and an increase in vascularity 207 of the dermis.14 208 209 Although interruption of capecitabine with dose reduction is the most important step in the 210 treatment of HFS, other measures are frequently employed. 15 Mild cases can be treated with 211 topical emollients and wound care. The rationale for using pyridoxine (vitamin B6) in HFS 212 came from the diagnosis of a similarly appearing skin disease in pyridoxine depleted rats.17 213 Pyridoxine is a water-soluble vitamin which is present in foods such as red meat, bananas, 214 beans and cereals. It is involved in amino acid metabolism, and also in carbohydrate and lipid 215 metabolism. In vivo, pyridoxine is converted mainly to pyridoxal 5'-phosphate which is the 216 active coenzyme in a number of metabolic transformations, including the conversion of 217 tryptophan to niacin or serotonin, the breakdown of glycogen to glucose-1- phosphate, the 218 conversion of oxalate to glycine, the synthesis of gamma- aminobutyric acid (GABA) within 219 the central nervous system (CNS) and the synthesis of heme. In adults, pyridoxine deficiency 220 mainly affects the peripheral nerves, skin, mucous membranes and the haemopoietic 221 system.18 There are no postulated mechanisms on how the vitamin may reverse the symptoms 222 of HFS, but there are published reports documenting its efficacy. To date, no prospective 223 randomized trials have been performed on the efficacy of pyridoxine in treating or preventing 224 HFS. 225 226 Pyridoxine was first used empirically by Vukelja et al, who treated one patient successfully 227 without interrupting 5-FU treatment.19 In a subsequent study involving patients with 228



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metastatic colorectal cancer receiving continuous infusional 5-FU, 16 of 25 patients 229 developed HFS which occurred at a median of 2 months after initial treatment. Five patients 230 were treated with pyridoxine 50mg or 150mg daily while continuing on the same 231 chemotherapy dose. Four of the five patients experienced improvement of HFS from grade 3 232 to grade 1, and chemotherapy was continued for a median of 6 months, compared to only 2.5 233 months in patients who did not receive pyridoxine. No adverse effects were reported in those 234 patients taking pyridoxine. 20 In a different study using a weekly regimen of 5-FU and 235 leucovorin, fourteen out of 52 patients developed HFS. Eleven of the patients received 236 pyridoxine 150mg daily without interruption of the chemotherapy and symptoms improved 237 for all of them within one week. Two patients who discontinued the pyridoxine while 238 continuing chemotherapy experienced recurrence of HFS symptoms within 2 weeks. 21 239 240 Laumann et al subsequently performed a retrospective multi-institutional chart review to 241 determine if pyridoxine was effective in ameliorating the symptoms of capecitabine-induced 242 HFS. Patients receiving doses of pyridoxine ≥200mg/day experienced a greater symptomatic 243 improvement in HFS compared to those receiving lower doses. The data from this pilot study 244 suggests that the addition of pyridoxine allows one to administer higher doses of capecitabine 245 without affecting the clinical efficacy of capecitabine. Higher doses of pyridoxine (>200mg 246 daily) may also be of greater clinical benefit. 22 Other advantages of pyridoxine include its 247 relative lack of adverse effects and its affordable cost. 248 249 More recently, East Asian patients were reported to have fewer toxicities than US patients in 250 a retrospective analysis of safety data from randomized single-agent fluoropyrimidine 251 clinical trials. Potential factors giving rise to this difference include genetic polymorphisms, 252 as well as differences in dietary folate intake. 23, 24, 25 253 254 255 Significance of the Study 256 257 Based on the limited data above, many patients who develop HFS on capecitabine receive 258 pyridoxine in addition to dose interruption or reduction. There are also clinicians who 259 empirically prescribe upfront pyridoxine for patients commencing capecitabine as primary 260 prophylaxis for HFS. Given that the use of capecitabine is set to increase, there is a need for 261 well-designed prospective controlled trials to investigate the role of pyridoxine in both 262 primary and secondary prophylaxis of HFS. 263 264 If pyridoxine is proven to be effective in preventing HFS, there will be less dose disruption 265 and reduction, and the efficacy of the treatment may be maintained. Patient’s quality of life 266 will also improve. If the findings from the study are negative, this should lead to a change in 267 clinical practice worldwide and result in cost savings. 268 269 270 4. PATIENT SELECTION 271 272 4.1 Inclusion criteria 273 • Patients receiving capecitabine for any malignancy, either in the adjuvant/neoadjuvant or 274

palliative setting 275 • Patients commencing capecitabine at a dose of ≥1000mg/m2 twice daily every 2 out of 3 276

weeks as single-agent chemotherapy. 277 • Signed informed consent 278



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• Male or female patients, age ≥ 18 years 279 • Life expectancy greater than 12 weeks. 280 (Concomitant radiotherapy, steroids or biological therapy eg trastuzumab, bevacizumab 281 permitted, as long as they do not cause HFS or neuropathy.) 282 283 4.2 Exclusion criteria 284 • Prior capecitabine chemotherapy 285 • Inability to provide informed consent 286 • Concomitant administration of drugs that can cause HFS eg docetaxel, liposomal 287

doxorubicin 288 • Concomitant administration of drugs that can cause neuropathy eg oxaliplatin, taxanes 289 • Pre-existing neuropathy confounding assessment of HFS 290 • Consumption of pyridoxine-containing preparations eg multivitamins, Vitamin B 291

complex 292 • Anticipated inability to follow-up patient for side-effects of chemotherapy 293 • Other dermatologic condition, that, in the opinion of the physician, may affect the hands 294

or feet or may complicate evaluation during study treatment 295 • Concurrent or planned use of over-the-counter products that contain urea or lactic acid eg 296

Aqua Care®, Medicated Calamine^® lotion (0.3%), Coppertone^® Waterproof Ultra 297 Protection Sunblock, Dr. Scholl's^® Smooth Touch deep moisturizing cream, 298 Depicure^® So Smooth Cream, Dove^® Moisturizing Cream Wash, Cetaphil^ 299 ®Moisturizing Cream 300

• Known allergy to pyridoxine and its incipients 301 • Concomitant administration of drugs reported to have drug interactions with pyridoxine 302

(including cycloserine, hydralazine, immunosuppressants, isoniazid, levodopa, 303 oestrogen or oestrogen-containing contraceptives, penicillamine, phenobarbitone, 304 phenytoin, pyrazinamide) 305

306 Patients will be asked to report and/or bring all concurrent medications, over-the-counter 307 preparations and topical applications which will be checked by the treating doctor and trial 308 nurses before entering the study. They will also be reminded of the need to avoid these 309 preparations at each visit. 310 Reasons for non-entry of potentially eligible patients will also be collected in a screening log 311 (appendix 20.5). The screening log may identify factors that steered patients away from the 312 trial, dissuaded physicians or investigators from entering patients into the trial, and will help 313 assess the generalisability of the findings. The log will not contain any details that can 314 identify patients. 315 316 317 5. STUDY DESIGN 318

319 Randomized double-blind placebo-controlled study 320 321 5.1 Treatment Plan 322 Patients commencing capecitabine at a dose of at least 1000mg/m2 twice daily every 2 out of 323 3 weeks will be randomized to receive either concomitant pyridoxine (200mg) or placebo 324 once daily orally for 21 days out of each treatment cycle. In the event that the patient cannot 325 start capecitabine together with pyridoxine or placebo immediately after informed consent 326 was obtained, a maximum dose delay of not more than 4 weeks is allowed. 327 328



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329 5.2 Study duration 330 • Until grade ≥2 HFS occurs, or 331 • Until capecitabine is ceased (due to disease progression, side effects or other reason), or 332 • For a maximum duration of 8 cycles (approximately 24 weeks). 333 334

335 6. OUTCOMES AND MEASURES 336 337 The primary outcome is the first incidence of grade 2 or greater HFS. The severity of HFS 338 will be graded 1 to 3 according to the National Cancer Institute (NCI) Common 339 Terminology Criteria for Adverse Events (CTCAE) version 3.0 outlined below. 340 341 Grade 0 No HFS 342 Grade 1 Minimal skin changes or dermatitis (eg erythema) without pain 343 Grade 2 Skin changes (eg bleeding, blisters, peeling, oedema) or pain not interfering 344

with function 345 Grade 3 Ulcerative dermatitis or skin changes with pain interfering with function 346 347 The secondary outcome of time to onset of grade 2 or greater HFS will be evaluated in days. 348 QOL will be assessed using EuroQOL EQ-5D questionnaire (attached in appendix). The EQ-349 5D, a short generic health-related quality of life (HRQOL) questionnaire, can derive 350 preference-based index scores. It is a five-item questionnaire for assessing HRQoL, plus a 351 visual analogue scale (VAS) of overall health status. It was specifically designed with 352 simplicity and cost-utility analysis in mind and has been tested and used in several disease 353 groups. In relation to other preference-based HRQOL instruments, the EQ-5D is relatively 354 short and easy to complete. 355 356 357 7. STUDY PROCEDURES 358 359 Clinician review 3-weekly (window period of ± 4 days is allowed) at the beginning of each 360 cycle (earlier if clinically indicated). Compliance with the medication regimen will be 361 assessed by tablet counts at each visit. If grade ≥2 HFS occurs, patient needs to be assessed 362 by clinician within 4 days of onset. 363 364 Baseline blood test for genotyping and serum, red cell folate and serum vitamin B12 365 levels. 366 Other routine blood tests (such as full blood count, biochemistry) and investigations before 367 commencement of chemotherapy are to be performed as clinically indicated at the discretion 368 of the treating physician. 369 370 Phone review by trial nurse weekly (during the weeks patients do not see their clinicians) 371 regarding compliance and HFS symptoms. 372 373 Daily HFS symptom record by patient; diary provided. 374 375 QOL assessment at baseline, at beginning of cycles 2, 4, 6, 8 and at the end of the study. 376 377 378



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379 380 8. INTERVENTIONS 381 382 8.1 Management of grade ≥2 HFS 383 384 Patients who develop HFS of grade 2 or greater severity will be withdrawn from the study. 385 Institution of daily pyridoxine with or without dose reduction of capecitabine may 386 subsequently occur at the clinician’s discretion. 387 388 8.2 Management of grade 1 HFS 389 390 Patients who develop grade 1 HFS may be treated with topical emollients if deemed 391 necessary by the treating oncologist. Type of emollient, frequency and duration of use need 392 to be fully documented. Dose interruption or reduction for grade 1 HFS is not permitted. 393 394 8.3 Chemotherapy dose modification, delay or interruption for other toxicities 395 396 Interruption, delay or modification of dose of capecitabine and/or other cytotoxic drug for 397 other toxicities or reason is permitted. Reason and dose need to be clearly documented. 398 399 8.4 Withdrawal criteria 400

• when Grade 2 or greater HFS occurs or 401 • if capecitabine is ceased due to disease progression, other side-effects or 402 • if patient decides to withdraw from the study. 403

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9. STUDY CALENDAR 407 408

* : Needs to be recorded by clinician at the beginning of the cycle or pre-study or at end 409 of study. 410

Pre-

stud

y

Cyc

le 1

Cyc

le 2

Cyc

le 3

Cyc

le 4

Cyc

le 5

Cyc

le 6

Cyc

le 7

Cyc

le 8

End

of

Stud

y

Date * * * * * * * * * *

Capecitabine dose * * * * * * * * * *

Informed consent *

Performance status * *

Demographics - Age - Gender - Race - Height - Weight

* * * * *

Underlying malignancy - Type - Stage

* *

Blood for genotyping, folate and vitamin B12 levels

*

Concurrent meds * * * * * * * * * *

Check compliance with capecitabine, pyridoxine or placebo

* * * * * * * * *

Reason for dose adjustment, delay or interruption, if any

* * * * * * * * *

Grade HFS * * * * * * * * * *

Other toxicities * * * * * * * * * *

QOL * * * * * * 411 412 10. GENOTYPING, FOLATE AND VITAMIN B12 LEVELS 413 414 Variability in response and toxicity to chemotherapy is determined by genetic factors and 415 also possibly by environmental and physiological factors. Pharmacogenetic studies have 416 identified gene variants that predict for efficacy and toxicity in the treatment of various 417 cancers including CRC. An 8ml sample of blood will be collected from each patient at the 418 same time as routine blood draw using cell preparation tube (CPT) at baseline. 419



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The sample will be identified by the study number with no direct identification of the patient 420 from the sample. DNA will be extracted using standardised methods and stored at minus 20 421 degree celsius for subsequent genotyping at Dr. Richie Soong’s laboratory. 422 Genotyping for polymorphisms of putative relevance to pyridoxine and capecitabine 423 metabolism (especially thymidylate synthase, thymidine phosphorylase, dihydropyrimidine 424 dehydrogenase, cytidine deaminase, carboxylesterase, methyltetrahydrofolate reductase) will 425 be performed using previously described techniques. 426 Additional 10ml of blood will also be taken for baseline serum and red cell folate and 427 vitamin B12 levels. 428 429 The incidence rate of the gene polymorphisms will be summarised and evaluated. 430 Potential associations between gene polymorphisms, folate and vitamin B12 levels and 431 clinical outcome will be performed using appropriate statistical methods. 432 433 434 11. STATISTICAL CONSIDERATIONS AND RANDOMISATION 435 436 11.1 Randomization 437 438 • Patients are randomized after the eligibility status has been fully determined and an 439

informed consent has been obtained. 440 441 • The randomization procedure will be carried out through telephone from the Clinical 442

Trials Office (CTO) of the Division of Clinical Trials & Epidemiological Sciences 443 (CTE), NCC. 444

445 • Block randomization will be used. Patients will be stratified according to gender and 446

use in adjuvant/neoadjuvant versus palliative setting. Within each stratum blocks of 447 consecutive patients will be formed. The Block length will be designed by a CTE 448 biostatistician and blinded to all other research personnel until study closure. 449

450 • Within each stratum and block, patients will be randomized with equal probability to 451

either: 452 ARM 1: concomitant pyridoxine 453 ARM 2: Placebo (control arm) 454

455 11.2 Sample size calculation 456 457 The null hypothesis of this study is that concomitant pyridoxine does not reduce the risk of 458 developing grade ≥2 HFS. The alternative hypothesis is that concomitant pyridoxine reduces 459 the risk of grade ≥2 HFS. 460 461 The overall incidence of grade ≥2 HFS for capecitabine single-agent cytotoxic therapy is 462 estimated to be 36-40%. Pyridoxine prophylaxis will be clinically worthwhile if it can almost 463 halve the incidence of grade ≥2 HFS. 464 465 To detect a reduction in the incidence of HFS from 36% to 20% with upfront pyridoxine at a 466 power of 80%, 123 patients per group will be required. We anticipate that up to 20% of the 467 patients may cease capecitabine before 4 cycles due to reasons such as disease progression 468 and intolerance of other side-effects. To make up for the difficulty in evaluating HFS in these 469



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patients, we intend to recruit extra 20% or 25 patients in each arm. Hence the target accrual 470 will be 296 patients in total with 148 patients for each arm. Interim analysis of results will 471 not be performed. 472 473 11.3 Statistical analysis 474 475 • Incidence of grade ≥2 HFS (%) 476 The incidence of grade ≥2 HFS (%) in each arm will be estimated with 95% confidence 477 intervals and will be compared using chi-square test. 478 Stratification will be performed according to gender and use in adjuvant/neoadjuvant versus 479 palliative setting. 480 481 • Time to the onset of grade ≥2 HFS (in days) 482

483 Time to the onset of grade ≥2 HFS (in days) will be estimated using the Kaplan-Meier 484 method. Difference in the two arms will be tested by the log-rank test. 485 486 • Quality of Life Analysis 487 488 The mean EQ-5D index (and standard error) at each time point for each arm will be 489 estimated. Differences between treatment arms in mean EQ-5D index at each time point will 490 be estimated and tested. However, all mean (95% CI) QOL values at each time point and 491 treatment arm will be plotted together and examined graphically. Changes in QOL will be 492 analysed with ANOVA tests. 493 494 • Intention-to-treat and per protocol analysis 495

496 The intention-to-treat principle will be applied in the main analysis. Per protocol analysis will 497 be used as secondary and sensitivity analysis. 498 499 500 12. ADVERSE EVENTS AND PROTOCOL VIOLATION POLICIES 501 502 If there are any adverse events suspected to be related to the treatment drug rather than the 503 cytotoxic drug or other medication or condition, they will be reported (see SAE report form 504 in appendix 21.3). 505 506 Protocol violation eg due to non-compliance or lack of follow-up or records, or patient 507 withdrawal as explained previously, will be reported. Patients will still be included in the 508 intent-to-treat analysis. 509 510 511 13. AGENT FORMULATION, DRUG INTERACTIONS, STORAGE AND 512

ACCOUNTABILITY 513 514 Pyridoxine is supplied as tablets of 50mg. 515 Formulation of placebo: tablets matching the pyridoxine tablets in size, colour, appearance 516 and nature of excipients (lactose, cornstarch, plastidon, magnesium stearate). 517 Source of pyridoxine and placebo supply: Beacons Pharmaceuticals Pte Ltd 518



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Drug interactions: cycloserine, hydralazine, immunosuppressants, isoniazid, levodopa, 519 oestrogen or oestrogen-containing contraceptives, penicillamine, phenobarbitone, phenytoin, 520 pyrazinamide 521 Storage (at room temperature) at National Cancer Centre (NCC) Singapore Pharmacy, and 522 these supplies will be accounted for at the site pharmacy. 523 Please refer to appendix for further information on pyridoxine. 524 525

526 14. LOGISTICAL CONSIDERATIONS 527

528 Site(s) to be involved and Study duration 529 Approximately 1,200 patients are prescribed capecitabine at National Cancer Centre in 530 Singapore annually. Accrual is expected to be about 12 patients per month. 296 patients will 531 be required for this study. Thus, patient accrual is expected to be complete within 2 years. 532 Additional time (approximately 6 months) is required to allow for the final patient entered 533 into the study to receive either pyridoxine or placebo daily for a maximum of 8 cycles of 3-534 weekly capecitabine chemotherapy. 535 Other hospitals in Singapore or overseas may also be invited to participate in this trial to 536 accrue patients over a shorter period of time. 537 538 Evaluable Patients and Dropouts 539 All patients registered in the study will be accounted for. Should a patient withdraw from the 540 study without having received the pyridoxine or placebo assigned, then a replacement patient 541 can be registered. 542 Patients evaluable for efficacy and adverse events are defined as: 543 - Patients who give informed consent to participate in the trial 544 - Patients who met all eligibility criteria 545 - Patients who have received pyridoxine or placebo. 546 547 Budget and Potential Funding Sources 548 The cost of pyridoxine and placebo tablets as well as their storage have been considered. 549 Funding is currently provided by the Singapore Cancer Society Research Grant 2006. 550 551 552 15. ADMINISTRATIVE ASPECTS 553

554 Monitoring, Auditing and Inspecting 555 The study will be monitored at regular intervals. Study procedures and study-related 556 toxicities will be monitored by the principal investigator and any study-related problems will 557 be evaluated and discussed with the investigators. 558 559 Patient Identification 560 All patients screened for the study will have their initials and birth date recorded. If a patient 561 is excluded from the study, the reason is to be documented in a screening log. The 562 investigator will be assigned a block of consecutive patient allocation numbers. Eligible 563 patients entering the study will be assigned a patient allocation number sequentially 564 beginning at the top of the allocation number list. The patient allocation number and patient's 565 initials are to be entered on all case report forms. 566 567 568 569



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Data Handling 570 Each patient’s data will be kept in individual files (case report forms). Data will be collected 571 by oncology research nurses and data managers. All data, protocols, amendments, 572 authorisations and correspondence will be stored at the trial centre(s). All data will be kept in 573 coded form and information will remain confidential. All data collection will be monitored to 574 ensure thorough and accurate collection. 575 576 Recording of Data 577 Case report forms (CRF) must be typewritten or printed legibly. The forms will be verified 578 against original records (and workbooks, if applicable). CRFs and all original data will be 579 readily available for review. 580 581 Record Retention 582 Copies of all pertinent information will be retained by the investigator for a period of 15 583 years following the date of study completion. 584 585 586 16. ETHICAL CONSIDERATIONS 587

588 Although pyridoxine is frequently used in the treatment or prevention of HFS from 589 capecitabine, the evidence is limited to mainly retrospective observational studies so far. 590 Pyridoxine, being a type of vitamin, rarely causes any side effects at the dosage used in this 591 study. This double-blind placebo-controlled trial will evaluate whether concomitant 592 pyridoxine can significantly prevent grade 2 or greater HFS in patients receiving 593 capecitabine. 594 595 Ethical Conduct of the Trial 596 The trial will be performed in accordance with the recommendations guiding physicians in 597 biomedical research involving human patients adopted by the 18th World Medical Assembly, 598 Helsinki, Finland, 1964 and later revisions. 599 600 Centralized Institutional Review Board (CIRB) 601 It is the responsibility of the investigator to obtain approval of the trial protocol and any 602 amendments of the protocol from the CIRB. The final approved protocol and the patient 603 information sheet and informed consent statement to be administered will be reviewed by the 604 CIRB. The Board's decision concerning conduct of the study will be made in writing to the 605 investigator. All correspondence with the CIRB should be filed by the investigator. The study 606 shall not commence until the CIRB has approved the study. 607 608 Patient Information and Consent 609 It is the responsibility of the investigator to give each patient (or the patient’s acceptable 610 representative) prior to inclusion in the trial, full and adequate verbal and written information 611 regarding the objective and procedures of the trial and the possible risks involved. The 612 patients must be informed about their right to withdraw from the trial at any time. A CIRB 613 approved written patient information sheet (included as an appendix to the protocol) must be 614 given to each patient before enrolment. An approved informed consent statement will then be 615 read and signed by the patient and the investigator. The written patient information must not 616 be changed without prior approval by the CIRB. Furthermore, it is the responsibility of the 617 investigator to obtain signed informed consent from all patients prior to inclusion in the trial. 618 619



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The patient will be provided with a copy of the signed informed consent statement. The 620 patient may withdraw from the study at any time without prejudicing future medical 621 treatment. Verification of a signed informed consent statement will be noted on the patient's 622 study CRF. 623 624 Modification of the Protocol 625 Any changes to the protocol affecting study objectives, study design, patient population, 626 study procedures or significant administrative aspects will require a formal amendment to the 627 protocol. The CIRB must approve such amendments before being instituted. 628 Administrative changes of the protocol are minor corrections and/or clarifications that have 629 no effect on the way the study is to be conducted. The CIRB may be notified of 630 administrative changes at the discretion of the investigator. 631 632 Privacy and Confidentiality 633 All information obtained as part of the research will remain confidential. Information will be 634 stored securely in coded format and password-protected, but will remain potentially 635 identifiable to investigators only. Information will not be reported to third parties without 636 individual patient consent. 637 638 639 17. PUBLICATION POLICY 640

641 It is the intention to publish the results of the study based on the final reports produced by the 642 principal investigators. No patients will be identified by name. Results will not be suppressed 643 by the investigators for commercial or other reasons. 644

645 646

18. INDEMNITY 647 648 There is an indemnity policy for investigator-initiated hospital-based research at National 649 Cancer Centre (NCC), Singapore. 650

651 652



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19. REFERENCES 653 654 655 1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2: 533-543. 656 657 2. Seow A, Koh WP, Chia KS, Shi LM, Lee HP, Shanamugaratnam K. Trends in cancer 658

incidence in Singapore 1968-2002. Singapore Cancer Registry, Report No. 6, 2004. 659 660 3. Twelves C, Xeloda Colorectal Cancer Group. Capecitabine as first-line treatment in 661

colorectal cancer. Pooled data from two large, phase III trials. Eur J Cancer 2002; 38 662 (Suppl 2): 15-20. 663

664 4. Twelves, C, Wong, A, Nowacki, MP, et al. Capecitabine as adjuvant treatment for stage 665

III colon cancer. N Engl J Med 2005; 352:2696. 666 667 5. Scheithauer W, Kornek GV, Raderer M et al. Randomised multicenter phase 2 trial of 668

two different schedules of capecitabine plus irinotecan as first line treatment in advanced 669 colorectal cancer. J Clin Oncol 2003; 21: 1307-1312. 670

671 6. Shields AF, Zalupski MM, Marshall JL et al. Treatment of advanced colorectal 672

carcinoma with oxaliplatin and capecitabine. Cancer 2004; 100: 531-537. 673 674 7. Grothey A, Jordan K, Kellner O et al. Capecitabine/irinotecan (Capiri) and 675

capecitabine/oxaliplatin (CapOx) are active second-line protocols in patients with 676 advanced colorectal cancer after failure of first-line combination therapy: results of a 677 randomized phase II study. Proc Amer Soc Clin Oncol 2004; 23: 3534. 678

679 8. Blum JL, Jones, SE, Buzdar AU et al. Multicenter Phase II Study of capecitabine in 680

paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17: 485-493. 681 682 9. O’Shaughnessy JA, Blum J, Moiseyenko V, Jones SE, Miles D, Bell D, Rosso R, 683

Mauriac L, Osterwalder B, Burger HU, Laws S. Randomized, open-label, phase II trial of 684 oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, 685 methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast 686 cancer. Ann Oncol. 2001 Sep;12(9):1247-54. 687

688 10. O’Shaughnessy J, Miles D, Vukelja S et al. Superior survival with capecitabine plus 689

docetaxel combination chemotherapy in anthracycline-pretreated patients with advanced 690 breast cancer: phase III trial results. J Clin Oncol 2002; 20: 2812-2823. 691

692 11. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous 693

palliative chemotherapy. J Clin Oncol. 1997 Jan; 15(1):110-5. 694 695 12. Borner MM, Schoffski P, de Wit R, Caponigro F, Comella G, Sulkes A, Greim G, Peters 696

GJ, van der Born K, Wanders J, de Boer RF, Martin C, Fumoleau P. Patient preference 697 and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and 698 leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer. 699 2002 Feb;38(3):349-58. 700

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13. Cassidy J, Twelves C, Van Cutsem E et al. First-line oral capecitabine therapy in 702 metastatic colorectal cancer: a favourable safety profile compared with intravenous 5-703 fluorouracil/leucovorin. Ann Oncol 2002; 13: 566-575. 704

705 14. Roche Products Pty Limited. Australian product information. 2002 706 707 15. Abushullaih S, Saad ED, Munsell M et al. Incidence and severity of hand-foot syndrome 708

in colorectal cancer patients treated with capecitabine: a single institution experience. 709 Cancer investigation 2002; 20(1): 3-10. 710

711 16. Van Cutsem E, Findlay M, Osterwalder B et al. Capecitabine, an oral fluoropyrimidine 712

carbamate with substantial activity in advanced colorectal cancer: results of a randomized 713 phase II study. J Clin Oncol 2000; 18: 1337-1345. 714

715 17. Gyorgy P, Eckardt R. Vitamin B6 and skin lesions in rats. Nature 1939; 144: 512. 716 717 18. MIMS Australia. Pyridoxine product information. MIMS 2002. 718 719 19. Vukelja SJ, Lombardo FA, James WD et al. Pyridoxine for the palmar-plantar 720

erythrodysesthesia syndrome. Ann Intern Med 1989; 9: 479-490. 721 722 20. Fabian CJ, Molina R, Slavik M et al. Pyridoxine therapy for palmar-plantar 723

erythrodysesthesia associated with continuous 5-fluorouracil infusion. Invest New Drugs 724 1990; 8: 57-63. 725

726 21. Mortimer JE, Anderson I. Weekly 5-fluorouracil and high-dose leucovorin: efficacy and 727

traetement of cutaneous toxicity. Cancer chemother pharmacol 1990; 44: 303-306. 728 729 22. Lauman M, Mortimer J. Effect of pyridoxine on the incidence of palmoplantar 730

erythroderma (PPE) in patients receiving capecitabine. Proc Amer Soc Clin Oncol 2001; 731 20: 1565. 732

733 23. Haller DG, Cassidy J, Clarke SJ et al. Potential regional differences for the tolerability 734

profiles of fluoropyrimidines. J Clin Oncol 2008; 26(13): 2118-2123. 735 736 24. Ho C, Vincent M, Jonker D, et al. Folate, SAH and SAM levels and the risk of severe 737

toxicity in colorectal cancer patients treated with 5-FU and folinic acid. ASCO 738 Gastrointestinal Cancers Symposium, January 22-24, 2004, San Francisco, CA (abstract 739 216). 740

741 25. Sharma R, Rivory L, Beale P, et al. A phase II study of fixed-dose capecitabine and 742

assessment of predictors of toxicity in patients with advanced/metastatic colorectal 743 cancer. Br J Cancer 2006; 94: 964-968. 744

745 746 747

748



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20. APPENDICES 749 750 20.1 ECOG performance status grading 751 752 ECOG 753

754 0 Able to carry out all normal activity without restriction 755 756 1 Restricted in physically strenuous activity but ambulatory and able to carry out light 757

work 758 759 2 Ambulatory and capable of all self care but unable to carry out any work; up and 760

about more than 50% of waking hours 761 762 3 Capable only of limited self care; confined to bed or chair more than 50% of waking 763

hours 764 765 4 Completely disabled; cannot carry out any self care; totally confined to bed or chair 766 767 768 769

770



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20.2 Pyridoxine product information 771 772 Pyridoxine Hydrochloride 773 774 MIMS Full Prescribing Information 775 MIMS revision date: 01/05/2002 776 Composition Active. Pyridoxine hydrochloride. 777 Inactive. Tablets. Lactose, gelatin, wheat starch, maize starch, propyl hydroxybenzoate, 778 microcrystalline cellulose, calcium stearate. 779 Injection. Water for injections. 780 781 Description 782 Chemical name: 3-hydroxy-4, 5-bis (hydroxymethyl)-2-picoline hydrochloride. Molecular 783 formula: C8H11NO3.HCl. MW: 205.64. CAS: 58-56-0. 784 White or almost white crystalline powder, or crystals. Pyridoxine has a slightly bitter, salty 785 taste. Soluble 1 in 5 of water and 1 in 115 of alcohol. Practically insoluble in chloroform and 786 in ether. 787 Actions Pyridoxine, pyridoxal and pyridoxamine are collectively known as the water soluble 788 B6 complex vitamins. Vitamin B6 is involved in amino acid metabolism, and also in 789 carbohydrate and lipid metabolism. In vivo, pyridoxine is converted mainly to pyridoxal 5'-790 phosphate which is the active coenzyme in a number of metabolic transformations, including 791 the conversion of tryptophan to niacin or serotonin, the breakdown of glycogen to glucose-1- 792 phosphate, the conversion of oxalate to glycine, the synthesis of gamma- aminobutyric acid 793 (GABA) within the central nervous system (CNS) and the synthesis of heme. 794 795 The recommended daily intake (RDI) for pyridoxine is dependent on the protein intake, and 796 the Australian RDI is based a requirement of vitamin B6 0.02 mg/g protein. In adults, 797 pyridoxine deficiency mainly affects the peripheral nerves, skin, mucous membranes and the 798 haemopoietic system. In children, the CNS is involved. Single deficiency of pyridoxine is 799 rare, and multiple vitamin deficiency is to be expected in any inadequate diet. 800 Pharmacokinetics. 801 Absorption. Pyridoxine, pyridoxal and pyridoxamine are readily absorbed from the 802 gastrointestinal tract, mainly in the jejunum, following oral administration. Normal serum 803 concentrations are 30 to 80 nanogram/mL. Gastrointestinal tract absorption may be 804 diminished in patients with malabsorption syndromes. 805 Distribution. Vitamin B6 is stored in the liver, however some amounts are stored in the brain 806 and muscle. Pyridoxal and pyridoxal phosphate, the principal forms of the vitamin present in 807 blood, are highly protein bound. Pyridoxal phosphate crosses the placenta and is excreted in 808 breast milk. The plasma concentrations in the fetus are five times greater than in maternal 809 plasma concentrations. 810 Excretion. Pyridoxine is converted to the active form pyridoxal phosphate. Riboflavin is 811 required for the conversion of pyridoxine phosphate to pyridoxal phosphate. In the liver, 812 pyridoxal phosphate is oxidised to 4-pyridoxic acid and is then excreted in the urine. 813 Pyridoxine has a half-life of approximately 15 to 20 days. Pyridoxine is removed by 814 haemodialysis. 815 Indications Treatment and prophylaxis of pyridoxine deficiency. 816 Contraindications Hypersensitivity to pyridoxine. 817 Precautions Long-term administration of pyridoxine has been associated with the 818 development of peripheral neuropathies. Peripheral neuropathy has generally been associated 819 with doses in excess of 2 g/day for two or more months, but has also been reported with 820



20

relatively low doses (50 mg/day). Neuropathic symptoms generally subside after the 821 withdrawal of pyridoxine. 822 Following the administration of pyridoxine in the treatment of seizures in neonates, severe 823 sedation and respiratory distress have been reported. Therefore, it is recommended that 824 resuscitation facilities be available when pyridoxine is given in these circumstances. 825 Pyridoxine hydrochloride injections should not be administered to patients receiving 826 levodopa unless a peripheral decarboxylase inhibitor such as carbidopa is also given (see 827 Interactions). 828 Carcinogenesis, mutagenesis, impairment of fertility. No data are available. 829 Use in pregnancy. Pyridoxine hydrochloride is a therapeutic good that has been exempted 830 from pregnancy classification. 831 There are no animal data available on the use of pyridoxine hydrochloride during pregnancy. 832 Problems in humans have not been documented with the intake of normal daily amounts of 833 pyridoxine. However, the use of large doses during pregnancy has resulted in pyridoxine 834 dependency syndrome in the neonate. 835 Use in lactation. There are no animal data available on the use of pyridoxine hydrochloride 836 during lactation. Pyridoxine is excreted in breast milk. Problems in the infant have not been 837 documented after the maternal intake of normal daily amounts of pyridoxine. A 838 concentration of pyridoxine in breast milk of approximately 240 nanogram/mL may be 839 expected if the maternal intake of pyridoxine is 2.5 to 5.0 mg/day. 840 Use in children. Problems in children have not been documented with the intake of normal 841 daily amounts of pyridoxine. 842 Interactions 843 Cycloserine. Cycloserine may increase the requirement for pyridoxine, and may cause 844 anaemia or peripheral neuritis, by acting as a pyridoxine antagonist or increasing the renal 845 excretion of pyridoxine. 846 Hydralazine. Hydralazine may increase the requirement for pyridoxine, and may cause 847 anaemia or peripheral neuritis, by acting as a pyridoxine antagonist or increasing the renal 848 excretion of pyridoxine. 849 Immunosuppressants. Immunosuppressants may increase the requirement for pyridoxine, and 850 may cause anaemia or peripheral neuritis, by acting as pyridoxine antagonists or increasing 851 the renal excretion of pyridoxine. 852 Isoniazid. Isoniazid may increase the requirement for pyridoxine, and may cause anaemia or 853 peripheral neuritis, by acting as a pyridoxine antagonist or increasing the renal excretion of 854 pyridoxine. 855 Levodopa. Administration of pyridoxine in doses of 5 mg or greater daily reverses the 856 therapeutic effects of levodopa by accelerating the peripheral metabolism of levodopa. This 857 reversal does not occur if a dopa decarboxylase inhibitor such as carbidopa is also given. 858 Oestrogen or oestrogen containing oral contraceptives. Administration of these agents may 859 increase the requirements for pyridoxine. 860 Penicillamine. Penicillamine may increase the requirement for pyridoxine, and may cause 861 anaemia or peripheral neuritis, by acting as a pyridoxine antagonist or increasing the renal 862 excretion of pyridoxine. 863 Phenobarbitone. Concurrent administration of phenobarbitone and pyridoxine may decrease 864 the serum phenytoin concentration. This effect has been reported with pyridoxine doses of 865 200 mg or greater daily for one month. 866 Phenytoin. Concurrent administration of phenytoin and pyridoxine may decrease the serum 867 phenytoin concentration. This effect has been reported with pyridoxine doses of 200 mg or 868 greater daily for one month. 869



21

Pyrazinamide. Pyrazinamide may increase the requirement for pyridoxine, and may cause 870 anaemia or peripheral neuritis, by acting as a pyridoxine antagonist or increasing the renal 871 excretion of pyridoxine. 872 Laboratory tests. Pyridoxine has been reported to produce false positive results in 873 urobilinogen determinations using Ehrlich's reagent. 874 Adverse Reactions Body as a whole. Allergic reactions have been reported occasionally. 875 Transient dependency symptoms (e.g. nervousness, tremors, abnormal ECG) have been 876 observed upon withdrawal after doses of 200 mg for more than three days. 877 Central nervous system. Headache, paraesthesia and somnolence have been reported. 878 Sedation and hypotonia have been observed in infants with pyridoxine dependency syndrome 879 treated with pyridoxine. Seizures have occurred after intravenous administration of very large 880 doses of pyridoxine. Prolonged administration of pyridoxine (for two or more months) may 881 cause peripheral sensory neuropathies, progressing from unstable gait and numb feet to 882 numbness and clumsiness of hands. Peripheral neuropathies have generally been associated 883 with long-term doses of 2 g/day or more but may also occur with doses as low as 50 mg/day. 884 Respiratory system. Dyspnoea and apnoea have been observed in infants with pyridoxine 885 dependency syndrome treated with pyridoxine. 886 Gastrointestinal. Nausea, abdominal pain, vomiting and loss of appetite have been observed 887 after high doses of pyridoxine. 888 Skin. Photosensitivity has been reported rarely. 889 Blood. Decreased serum folic acid, increased serum AST (SGOT). 890 Other. A transient burning or stinging may occur at the site of injection with intramuscular 891 and subcutaneous administration. 892 Dosage and Administration Pyridoxine hydrochloride can be administered orally, however 893 when oral administration is not feasible pyridoxine hydrochloride can be administered by 894 injection. 895 Pyridoxine hydrochloride injection may be administered intravenously, intramuscularly or 896 subcutaneously. There may be temporary burning or stinging pain at the site of subcutaneous 897 or intramuscular injection. 898 Withdrawal of long-term patients from pyridoxine therapy should be done with gradual dose 899 reduction. 900 Oral administration. Dosage. The usual dosage is 50 to 150 mg daily in divided doses. As a 901 nutritional supplement, it is usually administered in conjunction with other vitamins of the B 902 group. 903 Treatment of drug induced deficiency anaemia or neuritis. The usual dose of pyridoxine is 904 100 to 200 mg daily for three weeks, followed by the prophylactic oral administration of 25 905 to 100 mg daily. 906 Parenteral administration. Dosage. The usual dosage is 25 to 200 mg daily or as directed. 907 Prophylaxis and treatment of pyridoxine deficiency. Pyridoxine may be given as an 908 intravenous infusion as part of total peripheral nutrition. The dose should be individualised 909 according to patient need. 910 Treatment of drug induced pyridoxine deficiency. The usual dose of pyridoxine is 50 to 200 911 mg intramuscularly or intravenously per day for 3 weeks, followed by 25 to 100 mg/day as 912 needed. 913 Treatment of pyridoxine dependency syndrome in adults. Doses of 10 to 600 mg per day 914 intravenously or intramuscularly have been recommended by various sources. 915 Pyridoxine dependent seizures in infants. An initial dose of 10 to 100 mg intravenously or 916 intramuscularly is recommended, although doses of up to 200 mg intravenously have been 917 used. Severe sedation and respiratory distress have reportedly followed administration of 918 pyridoxine in the treatment of seizures in neonates. It is therefore recommended that 919 resuscitation facilities be available when pyridoxine is given in this setting. 920



22

Treatment of isoniazid poisoning. An amount of pyridoxine equal to the amount of isoniazid 921 ingested is recommended. The following dosage regimens have been suggested. An initial 922 dose of 5 g by intravenous infusion over 30 to 60 minutes followed by the remainder of the 923 dose by intravenous infusion over 1 to 2 hours; or an initial dose of 4 to 5 g by intravenous 924 infusion over 30 to 60 minutes followed by an additional 1 g intramuscularly every 30 925 minutes until the entire dose has been given. 926 Treatment of cycloserine poisoning. A dose of pyridoxine 300 mg or more per day, given 927 intramuscularly or intravenously, is recommended. 928 Treatment of hydralazine poisoning. A dose of 25 mg/kg is recommended. One-third of the 929 total dose should be administered intramuscularly, and the remainder is given by intravenous 930 infusion over three hours. 931 Overdosage Symptoms. The principle effect of pyridoxine overdosage is sensory axonal 932 neuropathy. Central effects have also been described. Neuropathy is most commonly 933 reported after chronic ingestion of 200 to 6,000 mg/day for months or years, but may also 934 occur after a single extremely large parenteral dose. These effects may be delayed by days or 935 weeks following completion of pyridoxine administration. Other symptoms of pyridoxine 936 overdose that have been rarely reported include nystagmus, exacerbation of seizures, lethargy 937 or insomnia, or signs of autonomic dysfunction (ileus, acute urinary retention). 938 Treatment. Treatment of overdose involves general supportive treatment, including 939 supporting respiratory and cardiac functions. 940 Through neurological testing it is also indicated if pyridoxine poisoning is suspected, 941 although neuropathy gradually improves following the removal of pyridoxine. Follow-up 942 should be extended for at least seven days after acute administration of potentially toxic 943 amounts, since delayed neurological effects have been reported. 944 Presentation Ampoules, (clear, colourless sterile solution for injection) 50 mg/1 mL: 5's. 945 Tablets, 25 mg (white, scored): 100's. 946 Storage Tablets. Store below 30 deg. C. Protect from light. 947 948

949



23

20.3 Adverse events report form 950 951

CTCAE Category

Adverse Event

Grade

Hospitalization/ Prolongation of Hospitalization

Comments



24

20.4 Participant Information Sheet and Informed Consent Form 952 953 954



INFORMATION FOR PARTICIPANTS 959 960 This is a clinical trial (a type of research study). Clinical trials include only patients 961 who choose to take part. Please take your time to make your decision. Discuss it 962 with your friends and family. If you do not wish to participate, your medical care will 963 not be affected in any way. 964 965 You are invited to take part in this study because you will be taking capecitabine 966 (Xeloda) chemotherapy. 967

968 969

WHY IS THIS STUDY BEING DONE? 970 971 The purpose of this study is to find out if taking daily pyridoxine (also known as 972 vitamin B6) can prevent a potential side-effect from capecitabine chemotherapy called 973 hand-foot syndrome (HFS). HFS is a condition affecting the hands and feet which can 974 range from mild pins and needles, redness and swelling to skin peeling which can be 975 painful and affect your activities. 976 977 HFS is usually managed by temporarily stopping or reducing the dose of capecitabine 978 chemotherapy. This research is being done because HFS is a common side-effect of 979 capecitabine, and we do not know if pyridoxine can prevent HFS. Pyridoxine is not 980 usually given to prevent HFS from happening, but it appears to have some effect in 981 treating HFS. 982 983 HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 984 985 Nearly 300 people like you across Singapore will take part in this study. 986 987 WHAT IS INVOLVED IN THE STUDY? 988 989 If you agree to take part in this study, you will be “randomised” to take either 990 pyridoxine or placebo orally once daily. Randomisation means that whether you get 991 pyridoxine or placebo will be determined by chance, like flipping a coin. Placebo is 992 an inactive pill made to look like the pyridoxine. Placebo is used in this study as 993 knowing whether someone is on pyridoxine or not can influence the reporting of HFS. 994 This is a double-blind study, that is, neither the staff (doctors and nurses) nor you will 995 know whether you are receiving the pyridoxine or the placebo. 996 997 The pyridoxine or placebo needs to be taken every day throughout each cycle of 998 capecitabine chemotherapy even though the capecitabine is taken for only 2 out of 999 every 3 weeks. 1000



25

If you take part in this study, you will continue to be seen by your doctor every 3 1001 weeks just as you normally will even if you do not join the study. You will still have 1002 the same investigations and blood tests as you would even if you were not in the 1003 study. However, a trial or research nurse will contact you via phone every week to see 1004 how you are going and to make sure that you take the medications correctly. 1005 1006 An extra 18ml or 18cc blood sample (approximately five teaspoons) is taken at the 1007 time of your routine blood tests before your first cycle of capecitabine. It will be 1008 examined for folate and vitamin B12 levels and genetic characteristics relating to how 1009 your body breaks down capecitabine or pyridoxine. These blood tests may help us to 1010 predict who is more likely to develop side effects from capecitabine. You will not be 1011 charged for these tests. 1012 1013 You need to let us know if you develop any problems with HFS so that your doctor 1014 can see you about it and adjust the treatment accordingly. You also need to keep a 1015 daily record of any symptoms of HFS. A symptom diary is what we generally 1016 encourage all patients taking capecitabine to keep, regardless of whether they are in a 1017 study or not. 1018 1019 If the HFS is mild, you may still continue with the chemotherapy and the pyridoxine 1020 or placebo in that instance. Please contact your doctor before you use any medications 1021 (including creams) for it. 1022 If the HFS is moderate (for example painful blisters, redness, swelling or peeling of 1023 the skin that doesn’t affect your activities) or severe (skin changes as described 1024 previously but painful enough to affect your function), you need to contact us so that 1025 your doctor can see you and adjust your treatment. 1026 1027 While you are in the study, you are not allowed to take any other medications or over-1028 the-counter preparations which contain vitamin B6 or pyridoxine or moisturizing 1029 creams as this will affect the results of the study. 1030 1031 HOW LONG WILL I BE IN THE STUDY? 1032 1033 We think you will be in the study for a maximum of approximately 24 weeks or 8 1034 cycles of capecitabine chemotherapy. However, if you get moderate to severe HFS as 1035 described earlier, you may be withdrawn from the study and your doctor may reduce 1036 or stop the capecitabine temporarily, with or without pyridoxine. You do not need to 1037 be in the study if you stop taking capecitabine earlier than planned for any other 1038 reason. You do not need to be followed up as part of the study after you have received 1039 8 cycles of the chemotherapy with capecitabine. You can still continue with the 1040 chemotherapy itself if your doctor decides it is appropriate. 1041 1042 You can stop participating at any time. However, if you decide to stop participating 1043 in the study, we encourage you to talk to the research nurse and your oncologist first. 1044 1045 WHAT ARE THE RISKS OF THE STUDY? 1046 1047 Pyridoxine, being a type of vitamin, rarely causes any side effects. However, some 1048 adverse effects have been reported, usually at a much higher dose than what we use in 1049 this study. They include nausea, vomiting, abdominal pain, loss of appetite, headache, 1050



26

tingling and drowsiness. Although a few cases of transient nervousness and tremor 1051 have been reported after stopping the pyridoxine, studies on larger series of patients 1052 have not confirmed such problems. 1053 1054 1055 WHAT ARE THE BENEFITS OF TAKING PART IN THE STUDY? 1056 1057 If you agree to take part in this study, there may or may not be direct medical benefit 1058 to you. We hope the information learned from this study will benefit other patients 1059 taking capecitabine in the future. 1060 All patients participating in the study will get 25% discount off the usual price of 1061 capecitabine tablets for up to six cycles while on the study, eg if each cycle of 1062 capecitabine costs $800, you will receive $200 discount every cycle. 1063

1064 WHAT OTHER OPTIONS ARE THERE? 1065 1066 Instead of being in this study, you have these options: 1067 Take the capecitabine chemotherapy as instructed without pyridoxine. 1068 Some oncologists recommend daily pyridoxine to patients taking capecitabine even 1069 before they get HFS. 1070 Please talk to your regular doctor about these and other options. 1071 1072 WHAT ARE THE COSTS? 1073 1074 The study investigator group will provide you with pyridoxine or placebo free of 1075 charge while you are being treated on this study. 1076 1077 Your participation in this study will not increase the amount of money you have to 1078 pay for your treatment at your institution. Apart from the 25% discount from the 1079 capecitabine chemotherapy, all other expenses, including the cost of routine standard 1080 examinations will be handled as if you were receiving standard treatment and not 1081 participating in a clinical trial. 1082 1083 Compensation for Participation 1084 1085 In the event that you suffer an adverse event or a medical accident during this study, 1086 treatment will be offered at the usual charge. The Hospital does not make any 1087 provisions to compensate trial subjects for research related injury. However, 1088 compensation may be considered on a case-by-case basis for unexpected injuries due 1089 to non-negligent causes. 1090 By signing this consent form, you will not waive any of your legal rights or release 1091 the parties involved in this study from liability for negligence. 1092 1093 WHAT ARE MY RIGHTS AS A PARTICIPANT? 1094 1095 Your participation in this study is voluntary. You may choose not to participate and 1096 receive treatment without affecting your health care/services or other rights. You are 1097 also free to withdraw from this study at any time. Withdrawal or refusal to participate 1098 will not prejudice your health care. 1099 1100



27

In the event new information becomes available that may affect the risks or benefits 1101 associated with this study or your willingness to participate in it, you or your legal 1102 representative will be notified so that you can make an informed decision whether or 1103 not to continue your participation in this study. 1104

1105 WHAT ABOUT CONFIDENTIALITY? 1106 1107 Your Privacy 1108 1109 Your rights of privacy will be maintained in the following manner: All information 1110 obtained about you during the study will be kept as confidential as legally possible 1111 and will be accessible only to your doctors, the investigators and any appropriate 1112 government agency. By signing the informed consent form you authorise this access 1113 to your records. Should the result of this study be published, neither your name nor 1114 any information from which you may be identified will be included. 1115 1116 Data associated with your participation in this study will be stored on paper records 1117 and computer, and analyzed using a computer. International regulations for the 1118 handling of computerized data will be followed. 1119

Confidentiality 1120

Your medical information will be kept confidential by the study doctor and staff and 1121 will not be made publicly available unless disclosure is required by law. 1122 1123 Data obtained from this study that does not identify you individually. 1124 1125 Your original medical records may be reviewed by the Singhealth Centralized 1126 Institutional Review Board (CIRB), and regulatory authorities for the purpose of 1127 verifying clinical trial procedures and/or data. By signing this consent form, you 1128 authorize the record review, information storage and data transfer described above. 1129 1130 1131 WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 1132 1133 If you have any questions about this study or your rights, please contact 1134 1135 Dr Yap Yoon Sim 1136 Department of Medical Oncology 1137 National Cancer Centre 1138 11 Hospital Drive, 1139 Singapore 169610 1140 Tel: 65-64368000; Fax: 65-62272759 1141 1142 or 1143 1144 Ms ….. 1145 Clinical Trials Coordinator 1146 Medical Oncology Clinical Trials Unit 1147



28

Ph: 1148 1149 This study has been reviewed by the Singhealth Centralized Institutional Review 1150 Board. Should you wish to discuss the project with someone not directly involved, in 1151 particular in relation to matters concerning policies, information about the conduct of 1152 the study or your rights as a participant, or should you wish to make a confidential 1153 complaint, you may contact the Secretary, Singhealth Centralized Institutional 1154 Review Board at (65) 6323 7515.. 1155 1156 If you would like to take part in this research study, please sign and date the attached 1157 consent form. Your signature indicates that you have decided to take part in this 1158 research study and that you have read and understand the information given above 1159 and explained to you. 1160 1161 You will be given a signed copy of this form to keep. 1162

1163 By signing this page, I am confirming the following: 1164 • The trial has been explained to me in a language __ _________________________ I 1165

(STATE THE LANGUAGE USED) 1166 • understand by _________________ _____ on _____ __________ . 1167 (NAME OF TRANSLATOR) (DATE) 1168 • I have read all the information in this Patient Information Sheet and Consent 1169

Form. 1170 1171 • All of my questions have been answered to my satisfaction. 1172 1173 • I voluntarily agree to be part of this research study, to follow the study procedures, 1174

and to provide necessary information to the doctor, nurses, or other staff members, 1175 as requested. 1176

1177 • I know that I can freely choose to stop being a part of this study at any time. 1178 1179 • I have received a copy of this Patient Information Sheet and Consent Form to keep 1180

for myself. 1181 1182 _________________________ ________________________ ____________ 1183 Name Signature Date 1184 1185 1186 _________________________ ________________________ ____________ 1187 Name of legal representative Signature Date 1188 1189 1190 _________________________ ________________________ ____________ 1191 Name of Investigator or Designee Signature Date 1192 1193 1194 _________________________ ________________________ ___________ 1195 Name of Witness Signature Date 1196



29



Biomarker Study 1201 1202 As part of the above research study, an extra 18ml or 18cc blood sample 1203 (approximately five teaspoons) is taken at the time of your routine blood tests before 1204 you commence capecitabine chemotherapy. It will be examined for folate levels and 1205 any genetic characteristics relating to how your body breaks down capecitabine or 1206 pyridoxine. You will not be charged for these tests. The blood samples will be coded 1207 with no direct identification of patients from the samples, and the information will be 1208 confidential. 1209 1210 If you agree to take part in this biomarker study, please sign and date the attached 1211 consent form. Your signature indicates that you have decided to take part in this 1212 research study and that you have read and understand the information given above 1213 and explained to you. 1214 1215 You will be given a signed copy of this form to keep. 1216

1217 By signing this page, I am confirming the following: 1218 • The trial has been explained to me in a language __ ________________________ I 1219

(STATE THE LANGUAGE USED) 1220 • understand by __________________ _____ on _____ _________ . 1221 (NAME OF TRANSLATOR) (DATE) 1222 • I have read all the information in this Patient Information Sheet and Consent 1223

Form. 1224 • All of my questions have been answered to my satisfaction. 1225 • I voluntarily agree to be part of this research study, to follow the study procedures, 1226

and to provide necessary information to the doctor, nurses, or other staff members, 1227 as requested. 1228

• I know that I can freely choose to stop being a part of this study at any time. 1229 • I have received a copy of this Patient Information Sheet and Consent Form to keep 1230

for myself. 1231 1232 _________________________ ________________________ ____________ 1233 Name Signature Date 1234 1235 _________________________ ________________________ ____________ 1236 Name of legal representative Signature Date 1237 1238 1239 _________________________ ________________________ ____________ 1240 Name of Investigator or Designee Signature Date 1241 1242 1243 _________________________ ________________________ ____________ 1244 Name of Witness Signature Date 1245 1246



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20.6 Capecitabine Dose Calculation according to Body Surface Area (BSA) 1247 1248 1249 Dose level ≥ 1000mg/m2 twice daily 1250 1251 NB: 1252 Due to the dosage capecitabine tablets come in (500mg and 150mg tablets), for 1253 convenience, some of the doses may be rounded down slightly. The minimum dose 1254 may be slightly below 1000mg/m2 twice daily, but investigators may prescribe a 1255 higher dose than the minimum dose. 1256 1257 Surface Area (m2)

Minimum Total Daily Dose (mg)

Minimum Twice Daily Dose (mg)

≤1.22 2300 1150 1.23-1.37 2600 1300 1.38-1.57 3000 1500 1.58-1.72 3300 1650 1.73-1.90 3600 1800 1.91-2.07 4000 2000 2.08-2.22 4300 2150 ≥ 2.23 4600 2300

1258



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1259 20.7 Euro-QOL (EQ-5D) QOL questionnaire 1260 1261 1262

1263 1264 1265



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1266 1267


Pyridoxine Protocol Version 6, 8 August 2011 · 21 Dr Tham Chee Kian Dr Wong Nan Soon 22 Dr Ooi Wei...

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Transcript of Pyridoxine Protocol Version 6, 8 August 2011 · 21 Dr Tham Chee Kian Dr Wong Nan Soon 22 Dr Ooi Wei...