| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diabetic Peripheral Neuropathic Pain (DPNP) |
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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 evaluate whether treatment at standard doses with duloxetine (60 mg/day) in combination with pregabalin (300 mg/day) is superior to a maximal dose of duloxetine (120 mg/day) or pregabalin (600 mg/day) given as monotherapy, over an 8-week period, in patients with diabetic peripheral neuropathic pain (DPNP), who don’t respond to a standard dose of either duloxetine or pregabalin after 8 weeks of initial treatment. Pain will be measured by the mean change on the Brief Pain Inventory (BPI) Modified Short Form 24-hour average pain item. |
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| E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of a duloxetine and pregabalin standard doses combination therapy versus a maximal dose of monotherapy with either pregabalin or duloxetine:
-on the following measures over an 8-week period: Mean change in items of the BPI Modified Short Form Severity and Interference portions, means on the CGI-I and PGI I scales, response rates defined, mean change in pain components on the NPSI questionnaire
-on mood symptoms (HADS).
-on functional/health outcomes as measured by mean changes on the SDS.
•To evaluate the safety of a duloxetine and pregabalin standard doses combination therapy versus a maximal dose of monotherapy with either pregabalin or duloxetine as measured by discontinuation rates, TEAEs and vital signs.
•To compare the effect of a maximal dose of duloxetine monotherapy versus a maximal dose of a pregabalin monotherapy versus a standard dose of duloxetine and pregabalin combination therapy on resource utilisation
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Male or female outpatients (at least 18 years of age).
[2] Pain due to bilateral peripheral neuropathy (caused by type 1 or type 2 diabetes mellitus. Pain must begin in the feet, with relatively symmetrical onset. Daily pain should be present for more than 3 months [assessed by questioning patient]. The diagnosis must be confirmed by a score of at least 3 out of 10 on the Michigan Neuropathy Screening Instrument at Visit 1.).
[3] Score of at least 4 on the 24-hour average pain severity score on an 11-point Likert scale (on BPI Modified Short Form) at Visit 1 and Visit 2.
[4] Patient is currently not receiving treatment for DPNP or was receiving treatment for DPNP, with a drug other than pregabalin or duloxetine, and completed the required washout (Section 9.7) prior to Visit 2.
[5] Patient has never received treatment with duloxetine or pregabalin. (However, a short course of less than 15 days of treatment, at any time previously, will be allowed.)
[6] Stable glycaemic control, as assessed by a physician investigator, and haemoglobin A1c (HbA1c) 12% at Visit 1.
[7] Patient has a level of understanding sufficient to provide written informed consent and to communicate with the investigator and site personnel.
[8] Patient is judged to be reliable, agrees to keep all appointments for clinic visits, and agrees to participate in recording responses to questionnaires and other instruments used in this study, as well as all other protocol procedures.
[9] All females of child-bearing potential must test negative for pregnancy at Visit 1, based on a serum pregnancy test. Females of child-bearing potential (not surgically sterilised and between menarche and 1 year post-menopause) must agree to use a 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 study drug. Examples of reliable methods include use of oral contraceptives or Depo Provera Contraceptive Injection (sterile medroxyprogesterone acetate suspension, Pharmacia & Upjohn), abstinence, partner with vasectomy, diaphragm with contraceptive jelly, condom with contraceptive foam, and intrauterine
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| E.4 | Principal exclusion criteria |
[10] Have a known hypersensitivity to duloxetine or pregabalin or any of the inactive ingredients or have any contraindication for the use of duloxetine or pregabalin.
[11] Have uncontrolled narrow-angle glaucoma.
[12] Have previously completed or withdrawn from this study or any other study investigating duloxetine or pregabalin or have previously been treated with duloxetine or pregabalin (with the exception of a short course of duloxetine or pregabalin for <15 days). Note: Patients who have been previously screened for a duloxetine study other than this study and never received study drug will be eligible for this study if they meet all current entry criteria.
[13] Have received treatment with a monoamine oxidase inhibitor (MAOI) within 14 days prior to Visit 2, or have a potential need to use a MAOI during the study or within 5 days after discontinuation of study drug.
[14] Have received fluoxetine within 30 days prior to Visit 2.
[15] Have acute liver injury (such as hepatitis) or severe cirrhosis (Child-Pugh Class C).
[16] Have a serum creatinine 1.5 mg/dL or a creatinine clearance <60 mL/min, at Visit 1.
[17] Are judged clinically by the investigator to be at suicidal risk or as defined by a score of 2 or greater on Question 9 of the BDI-II, at Visit 1 or Visit 2.
[18] Have current, or a history of, substance abuse or dependence within the past year (e.g. amphetamines, barbiturates, cannabis, cocaine and opiates), excluding nicotine and caffeine.
[19] Exclusion criterion [19] has been deleted.
[20] Women who are breast-feeding.
[21] Have a historical exposure to drugs known to cause neuropathy (for example, vincristine), or a history of a medical condition, including pernicious anaemia and hypothyroidism, that could have been responsible for neuropathy.
[22] Have pain that cannot be clearly differentiated from or conditions that interfere with the assessment of the DPNP. Examples of painful conditions that could be confused with diabetic neuropathy pain include peripheral vascular disease (ischaemic pain); neurological disorders unrelated to diabetic neuropathy (for example, phantom limb pain from amputation); skin condition in the area of the neuropathy that could alter sensation (for example, plantar ulcer); other painful conditions (for example, arthritis).
[23] Are investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
[24] Are employed by Lilly or Boehringer Ingelheim (BI) (that is, employees, temporary contract workers, or designees responsible for conducting the study). Immediate family of Lilly or BI employees may participate in Lilly/BI-sponsored clinical trials, but are not permitted to participate at a Lilly facility.
[25] At the time of study entry (Visit 1), are currently enrolled in, or have been discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
[26] Have serious or unstable cardiovascular, hepatic, renal, respiratory or haematological illness; symptomatic peripheral vascular disease; a history of seizure disorder; or other medical (including unstable hypertension and not clinically euthyroid) or psychological conditions that, in the opinion of the investigator, would compromise participation or be likely to require hospitalisation during the course of the study.
[27] Have a history of frequent and/or severe allergic reactions with multiple medications.
[28] Are currently taking any excluded medications that cannot be discontinued at Visit 1 (see Section 9.7).
[29] Have any exclusion criteria required by local law.
[30] Have received non-pharmacological treatment for pain within 14 days prior to Visit 2, or do not agree to abstain from non-pharmacological treatment during the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The BPI Modified Short Form (Cleeland and Ryan 1994) is a self-reported instrument that measures the severity of pain and the interference of pain on function. The primary efficacy measure will be the BPI Modified Short Form 24-hour average pain item score. This measures the severity of pain over the previous 24 hours |
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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 | Yes |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 35 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 62 |
| 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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| The end of the trial is 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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