| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY SYMPTOMS |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029331 |
| E.1.2 | Term | Neuropathy peripheral |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate the time to onset of moderate-severe persistent paresthesic positive symptoms of chemotherapy-induced neuropathy defined as a minimum score ≥ 4 assessed with the Numeric Rating Scale (NRS) from the onset of chemotherapy or emergence of a chemotherapy dose reduction or delay of chemotherapy cycle due to severity of chemotherapy-induced neuropathy.
The persistent paresthesic positive symptoms will be measured by a modified NRS (Numeric Rating Scale) which assesses paresthesia rather than pain. |
|
| E.2.2 | Secondary objectives of the trial |
•time to onset of any paresthesic positive symptoms of the chemo induced neuropathy from onset of chemo
•time to onset of persistent dysesthesic and pain positive symptoms of chemo induced neuropathy from initial chemotherapy as measured using the modified NRS
•time to onset of acute positive neuropathic symptoms of the chemo induced neuropathy from initial chemotherapy to the last cycle
•parasthesic, dysesthesic, and pain symptoms score over each chemo cycle
•proportion of subjects experiencing positive neuropathic symptoms in each treatment group at endpoint
•time to onset of the chemo induced cold intolerance developed from initial chemotherapy to the last cycle
•subjects’ pain interference of function as measured by the mBPIsf
•effect of pregabalin on self-reported symptoms of depression and anxiety in subjects as measured by the HADS
•effect of pregabalin on sleep interference in subjects as measured by the DSI
•subjects’ overall health status as measured by the EQ5D
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients between 18-80 years of age
2. Females of childbearing potential must have a negative serum ß-HCG pregnancy test and be practicing an effective form of contraception. Complete abstinence may be considered acceptable, but must first be discussed on a case-by-case basis with the Pfizer monitor prior to any screening tests or procedures for the study.
3. A confirmed diagnosis of Colorectal Cancer
4. Independent of this protocol, the patient has decided to receive standard of care for the treatment of cancer with oxaliplatin combined with 5-fluorouracil/folinic acid (5-FU/FA) for a minimum of 9 cycles
5. The patient has a performance status score of 0-2 (inclusive) as measured by the ECOG Performance Scale.
6. NRS (Numeric Rating) score = 0 for paresthesia, dysesthesia
7. Signed and dated informed consent will be obtained from each subject (only include those able to consent) in accordance with the local regulatory and legal requirements
8. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures. Subjects who are willing, but need assistance for self administered questionnaires may be considered acceptable, but must first be discussed on a caseby- case basis with the Pfizer monitor prior to any screening tests or procedures for the study. |
|
| E.4 | Principal exclusion criteria |
1. Pregnant or lactating women, or women of childbearing potential not practicing an effective method of contraception
2. Any treatment with previous chemotherapeutic agents with neuropathic effects. Refer to appendix M.
3. Any history of known brain metastases, spinal cord compression, or evidence of symptomatic brain or leptomeningeal carcinomatosis
4. Presence of neuropathic pain or peripheral polyneuropathy or identified causes of painful paresthesia including radiotherapy-induced or malignant plexopathy, lumbar or cervical radiculopathy existing prior to baseline
5. A current medical diagnosis that could potentially lead to the development of neuropathic pain over the course of the study (e.g. HIV neuropathy, herpes zoster) or pre-existing peripheral neuropathy of another etiology, including: (e.g. B12 deficiency, AIDS, monoclonal gammopathy,diabetes, heavy metal poisoning, amyloidosis, syphilis, hyperthyroidism or hypothyroidism, inherited neuropathy)
6. A diagnosis of dihydro-pyrimidine-dehydrogenase (DPD) deficiency prior to baseline
7. A medical diagnosis of renal failure prior to baseline
8. History of neoplasm other than colorectal carcinoma that could potentially lead to previous neuropathic pain. Subjects with previous histories of neoplasms may be considered acceptable, but must first be discussed on a case-by-case basis with the Pfizer monitor prior to randomization in the study, except for: radically treated non melanoma skin cancer or in situ carcinoma of cervix.
9. Recent history of myocardial infarction within 6 months from study entry, uncontrolled hypertension or high risk uncontrolled arrhythmias, unstable angina pectoris
10. A previous history of intolerance or hypersensitivity to pregabalin, gabapentin, or other drugs structurally similar to the neurotransmitter GABA
11. Creatinine Clearance <60 mL/min (from serum creatinine).
12. Hematological values: WBC < 2.5 X 103/µl ; Platelets < 100 X 103/µl at screening
13. Clinically significant abnormal 12-lead electrocardiogram (ECG).
14. Abuse of illicit drugs or alcohol within the past 2 years
15. In the judgment of the investigator the subject is unable or unlikely to follow the protocol, or otherwise might not be suitable for the study
16. In the judgment of the investigator, any subject unable to understand the nature, scope, procedures and possible consequences of the study and/or evidence of an uncooperative attitude
17. Participation in any other studies involving investigational or marketed products, concomitantly or within 30 days prior to entry in the study
18. Previous use of gabapentin or pregabalin within 30 days prior to randomization or likelihood of engaging in these treatments during the study period
19. Subjects taking the following concomitant medications:
≤ One month stable doses of TCAs, antidepressants, paracetamol,
≤ 2 weeks stable doses corticosteroids, NSAIDs,
≤ One month stable use of hypnotics/sedatives such as zopiclone, eszopiclone, ketazolam, zolpidem, zaleplon, triazolam, Dosing frequency of 3-7 times/ week is considered stable,
≤ One month stable use of benzodiazepines such as alprazolam, clonazepam, diazepam, flurazepam, lorazepam, midazolam, quazepam, triazolam, and temazepam. Medications initiated as standard treatment with chemotherapy will be considered stable at non-flucuating dosages during the trial.
20. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration ormay interfere with the interpretation of trial results and, in the judgment of the investigator, would make the subject inappropriate for entry into this trial.
21. Any patients who are not suitable to be treated with either Oxaliplatin and/or 5-FU/FA or pregabalin according to the respective local labeling |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The time to onset of moderate-severe persistent paresthesic positive symptoms of chemotherapy-induced neuropathy defined as a minimum score ≥ 4 assessed with the Numeric Rating Scale (NRS) from the onset of chemotherapy. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 15 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 15 |
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