E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Central neuropathic pain due to Multiple sclerosis |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054095 |
E.1.2 | Term | Neuropathic pain |
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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 assess the efficacy of duloxetine 60 mg once daily (QD) compared with placebo on the reduction of central neuropathic pain severity as measured by the weekly mean of the daily 24-hour average pain scores in patients with central neuropathic pain due to MS assessed using an 11-point Likert scale and collected via daily patient diary at the end of 6 weeks of treatment. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate response to treatment with duloxetine versus placebo using 2 response criteria, a 30% or 50% reduction, in the weekly 24-hour average pain scores described in the primary objective • To assess the efficacy of duloxetine versus placebo as measured by:PGI-Improvement scale,the weekly mean of the 24-hour worst, least, and night pain scores assessed using an 11-point Likert scale and collected via daily patient diary,BPI– Severity and Interference,CGI-Severity • To assess the impact of treatment with duloxetine versus placebo on patient-reported health outcomes, as measured by the MS-QOL-54 • To assess the safety of duloxetine versus placebo treatment-emergent adverse events, discontinuation adverse events, solicited questioning of suicide-related events, and suicide risk as assessed the C-SSRS, laboratory assessments, and vital signs. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Addendum (1) 15 August 2008
All patient enrolled in the clinical study F1J-US-HMFR will be invited to participate in this substudy. Patient participation in this substudy is optional. Eligible patients who choose to participate will consent to the collection and storage of blood for DNA extraction for research. DNA samples will be stored by the central laboratory located in the United States. Stored samples will retain the patient identifier and, therefore, will not be stored indefinitely. Samples will be stored for a maximum of 5 years after last patient visit for the study; any sample remaining at that time will be destroyed. Cells from stored samples will not be made to grow indefinitely in the laboratory (immortalized). In addition, the patient's entire genetic makeup will not be determined from the samples. The primary objective of this addendum is to collect and store sample(s) of whole blood for future research. The research on stored samples from this study will involve looking at genetic variants in DNA associated with pain in multiple sclerosis, depression, and treatment with duloxetine or other agents used to manage chronic pain. DNA samples may be analyzed for genetic variants (polymorphisms and/or single-nucleotide polymorphisms [SNPs]) that include, but are not limited to, the serotonin transporter (5-HTT), norepinephrine transporter (NET), adrenergic receptors, COMT and genes associated with drug metabolism and transport.
Protocol Addendum (2) 4 December 2008 - Measurement of Plasma Levels of Brain-Derived Neurotrophic Factor (BDNF) Protocol Addendum
All patient enrolled in the clinical study F1J-US-HMFR will be invited to participate in this substudy. Patient participation in this substudy is optional. The primary objective of this addendum is to collect plasma for assay of BDNF levels for research from subjects with central neuropathic pain due to MS treated with duloxetine or placebo and to determine via an exploratory secondary analysis whether pain reduction with study drug is correlated with changes in plasma levels of BDNF. The secondary objective is to evaluate via an exploratory secondary analysis the correlation between levels of BNDF and pain reduction with study drug in subjects with and without major depressive disorder. |
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E.3 | Principal inclusion criteria |
[1] Present with central neuropathic pain due to MS based on the disease diagnostic criteria [2] Are male or female outpatients at least 18 years of age at the time of consent [3] Have a score of 4 or greater on the daily 24-hour average pain score (0- 10) for at least 4 of the 7 days prior to Visit 2 [4] Females must test negative for pregnancy at Visit 1. Females of childbearing potential must agree to utilize medically acceptable and reliable means of birth control as determined by the investigator during the study and for 1 month following the last dose of the study drug [5] Have an educational level and degree of understanding such that the patient can communicate intelligibly [6] Are judged to be reliable and agree to keep all appointments for clinic visits, tests, and procedures required by the protocol [7] Complete the daily diaries for at least 70% of the days between Visit 1 and Visit 2 [8] Patients may continue other prescription and non-prescription analgesic medications as long as the dose has been stable for 1 month prior to Visit 1, and they agree to maintain that stable dose throughout the study. Patients will NOT be allowed to change doses of concomitant analgesics during the study [9] Diagnosis of MS at least 1 year prior to Visit 1 as determined by MacDonald or Poser criteria. [10] Clinical stability as determined by an absence of MS exacerbation or change in disease modifying therapy for the 3 months prior to Visit 1. [11] Daily central neuropathic pain due to MS present for a minimum of 3 months prior to Visit 1 |
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E.4 | Principal exclusion criteria |
[12] Are investigator site personnel directly affiliated with this study and/or their immediate families [13] Are Lilly employees [14] Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry [15] Are currently in a clinical trial of MS disease-modifying therapy [16] Have pain that cannot be clearly differentiated from causes other than MS [17] Have previously completed this study, withdrawn from any duloxetine study, or have been intolerant to previous duloxetine treatment. Note: Patients who have screen-failed for the reason of previous exposure to duloxetine may be reconsidered for this study. [18] Have previously demonstrated lack of response to an adequate trial of duloxetine per investigator opinion. [19] Are unwilling to comply with the use of a data collection device to directly record data from the patient. For those patients who do not have enough fine motor control to enter data directly into the device, a designated assistant may be used for data entry. The assistant must be the same person for all data entries. The designated assistant may not be site personnel or personnel affiliated with the study. [20] Any current or historical DSM-IV diagnosis of mania, bipolar disorder, psychosis, or schizoaffective disorder [21] History of DSM-IV-TR substance abuse or dependence within the 6 months immediately prior to Visit 1, excluding nicotine and caffeine. For purposes of this study, prior or current use (at Visit 1) of dronabinol (Saltivex) for MS or MS pain will not be considered to meet the DSm-IV criteria for substance abuse. However, use of this medication may be subject to other restrictions (see concomitant medication list for excluded medications). [22] Are taking any excluded medications that cannot be discontinued at Visit 1 (see concomitant medication list for excluded medications). [23] Have had treatment with a MAOI within 14 days of randomization or the potential need to use an MAOI during the study or within 5 days of discontinuation of study drug [24] Have a positive urine drug screen for any substance of abuse or excluded medication [25] Are pregnant or breast-feeding [26] Have serious cardiovascular, hepatic, renal, respiratory, or hematologic illness, or other medical or psychiatric condition that, in the opinion of the investigator, would compromise participation or be likely to lead to hospitalization during the course of the study. [27] Have elective surgery planned during the trial. [28] Have a history of recurrent seizures other than febrile seizures. [29] Are judged clinically by the investigator or are identified by the C-SSRS or BDI-II question 9 to be at suicidal risk prior to starting study drug. Patients will need to be evaluated by the investigator and/or a psychiatrist if they exhibit suicidality as assessed by the C-SSRS or BDI-II question 9 at any time after randomization. [30] Have uncontrolled narrow-angle glaucoma. [31] Have acute liver injury or severe cirrhosis [32] Have known hypersensitivity to duloxetine or any of the inactive ingredients [33] Have frequent or severe allergic reactions to multiple medications [34] Current DSM-IV-TR Axis I alcohol or eating disorders or PTSD as determined either by patient history or by diagnosis using specific modules of the MINI |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy measure is the weekly mean of the 24-hour average pain severity assessed daily by each patient, via daily diary, using an 11-point Likert scale. |
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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 | Yes |
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 | Yes |
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 | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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
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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 | 17 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 17 |