1. Διπλωματική Εργασία στο θέμα:
Πρόγραμμα Μεταπτυχιακών Σπουδών (ΠΜΣ) «Μεθοδολογία Βιοϊατρικής Έρευνας, Βιοστατιστική και Κλινική Βιοπληροφορική»
Διπλωματική Εργασία στο θέμα:
“ Draft a protocol for a randomized clinical trial to assess the efficacy of lamotrigine in the treatment of chemotherapy-induced periphreral neuropathy ”
Τσιμπούρα Παρασκευή
Ακαδημα'ι'κό έτος:
Επιβλέπων:
κ. Ζιντζαράς Η.

2. Protocol design
A protocol to conduct a randomized , double- blind, multi-center, placebo controlled clinical trial to study the efficacy of lamotrigine in the treatment of CIPN
The design was drawn in accordance to the E6 ICH-GCP template

3. CIPN
Very common ( prevalence: 60-90% ) dose- limiting toxicity of chemotherapeutics
Caused by platinum-based compounds, vinca alkaloids, taxanes and proteasome inhibitors
Mainly sensory but also motor and autonomic nerve damage
Assessed and graded by several scores with the TNS being the most recent and seemingly most accurate one

4. Lamotrigine Anti-epileptic agent
Evidence of lamotrigine being effective in neuropathic pain of various causes
Not enough research on its efficacy in CIPN
Study ( author, year )
Neuropathic pain
Conclusion- Effect of lamotrigine
Eisenberg et al, 1998
McCleane, 1999
McCleane, 2000
Eisenberg et al, 2001
Vu, 2004
Backonja and Serra, 2004
Singleton et al, 2005
Vinik et al, 2007
Coderre et al, 2007
Chong and Hester, 2007
Diabetic neuropathy
Potentially effective
no effect
may be effective
effective
first-line or adj. Therapy
first-line therapy
may reduce hyperalgesia

5. Study design Randomized, double-blind, placebo controlled, phase III
Total duration 24 weeks ( until 10th week dose escalation, until 20th week maximum dosis therapy and after that 4 weeks for drug discontinuation ) for each patient and 52 weeks for each centre ( 28 weeks for patient recruitment)

6. Flowchart of the study design

7. Objectives
Primary:
Improvement of neuropathic pain measured by the NRS score
Secondary:
1. Improvement of other neuropathic symptoms by using the Total Neuropathy Score
2. Improvement of overall quality of life measured by the patient-filled EORTC QLQ - CIPN20

8. Inclusion criteria 1) Disease characteristics:
- Diagnosis of cancer
- Received or currently receiving neurotoxic chemotherapy
- Pain or symptoms of peripheral neuropathy for at least 1 month with NRS>4 and TNS>1
2) Patient characteristics:
- 18 and over
- Life expectancy at least 6 months
- Bilirubin < 2 times ULN and Creatinine < times ULN
- Fertile patients must use effective contraception
- Able to complete questionnaires
3) Prior Concurrent Therapy:
- Vinca alkaloids or taxanes or proteasome inhibitors or platinum-based combounds or combination
- >7 days prior methotrexate or other dihydrofolate inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, opioid analgesics, anticonvulsants, adjuvant analgesics, topical analgesics, amifostine
- >30 days since prior investigational agents for pain control
- No other concurrent investigational agents for pain control

9. Exclusion criteria Pregnant or nursing Positive pregnancy test
Prior allergic reaction or intolerance to lamotrigine
Extreme difficulty swallowing pills
Other identified causes of painful paresthesia preceding chemotherapy, eg radiation or malignant plexopathy, lumbar or cervical radiculopathy
Pre-existing peripheral neuropathyof any other etiology, eg AIDS, cyanocobalamine deficiency, diabetes, hyper- or hypothyroidism,etc
Significant psychiatric illness

10. Statistical considerations (1)
Sample size:
2 arms , 60 patients in each arm ( drug and placebo )
Power 80%
Patient enrollment to avoid study withdrawal >10%
Stratification:
3 strata in each arm:
- Type of chemotherapeutic agent
- Gender
- Enrollment during or after completion of chemotherapy

11. Statistical considerations (2)
Per protocol analysis as well as ITT analysis
Primary end point: mean difference of NRS score between baseline and final score applying a co-variation analysis ( ANCOVA ) with treatment set as a factor and baseline NRS score as a co-variate.
Null hypothesis: equality of lamotrigine and placebo
Secondary end points: mean differences of TNS and QLQ-CIPN20 between baseline and final values also applying an ANCOVA in the same way.
Per stratum analysis
Parametric ( independent t- test for numerical or chi-square for categorical) or non-parametric tests ( Mann- Whitney U for numerical or Fisher's exact test for categorical ), for patient demographic data and baseline Cr and TBIL values
Chi-square analysis to compare the occurence of adverse reactions

12. Management of AEs
ADRs thoroughly documented and quickly reported to sponsor
SAEs reported within 24 hours to sponsor and followed up until resolvement
Pregnancy considered as SAE

13. Ethics and Publication
Accordance to Declaration of Helsinki, ICH GCP, international norms and local legal demands
Credibility and confidentiality of medical data
Thorough patient information about the clinical trial, goals , risks and dangers, their rights , etc
No protocol deviations or changes without the National Ethics Committee's approval except urgent reasons concerning patients' safety
Patient enrollment only after signing the IC
The study's data is property of the sponsor
No early publication or discussion of the results without the sponsor's written agreement.

14. Thank you!