E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
PAINFUL DIABETIC PERIPHERAL NEUROPATHY |
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E.1.1.1 | Medical condition in easily understood language |
DPN is a peripheral nerve disorder sometimes caused by diabetes |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012683 |
E.1.2 | Term | Diabetic peripheral neuropathy |
E.1.2 | System Organ Class | 100000004852 |
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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 the efficacy of pregabalin compared with placebo for the symptomatic relief of DPN pain in subjects with painful DPN who use one NSAID (including COX 2 inhibitors) primarily for the treatment of conditions other than DPN pain. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of pregabalin compared with placebo treatment to improve subject global assessment, sleep, quality of life associated with DPN, and time to loss of pain response.
• To evaluate the safety and tolerability of pregabalin.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study.
1. Diagnosis of type 1 or 2 diabetes mellitus with current hemoglobin A1C levels of ≤11%. Subject is to be on an antidiabetic treatment regimen and it must be stable for the 30 days prior to Visit 2.
2. Diagnosis of painful, diabetic distal symmetrical sensorimotor polyneuropathy for at least 3 months.
3. Currently treated with one NSAID (including COX 2 inhibitors) for a co morbid pain condition with a regular dose (≥4 days/week) for at least 4 weeks prior to screening, and the ability to maintain the same treatment regimen during the study. The NSAID use must not be primarily for treating the subject's DPN pain.
4. Meet the following 2 criteria demonstrating inadequate pain control:
• A score of ≥ 4 on the one week recall, 11 point numerical rating scale for pain (Weekly NRS Pain) at screening, Visit 1.
• AND at Visit 2, subjects must have completed at least 4 daily pain diaries over the past 7 days (baseline) and have an average daily pain score of ≥4 on the 11 point numeric rating scale for pain (Pain Diary).
5. Men or women who are at least 18 years of age.
6. Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
7. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
8. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures including the training and completion of the daily pain and sleep diaries using IVRS. |
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E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study.
1. Pain fluctuation ≥4 points determined by the difference between the highest and lowest pain score by Pain Diary during baseline period (the last 7 days prior to V2).
2. Have failed pregabalin treatment due to lack of efficacy at therapeutic dose(s), have intolerance to pregabalin or any pregabalin ingredient, have used pregabalin within the last 30 days (prior to V1).
Note: If the subject has taken pregabalin and discontinued for reasons other than lack of efficacy or intolerance (eg, economic burden), then they will be eligible.
3. Participated in a previous or ongoing pregabalin clinical trial.
4. Neurologic disorders unrelated to diabetic neuropathy that may confound the assessment of distal neuropathic pain.
5. Skin conditions in the area affected by the neuropathy that could alter sensation.
6. Other pain conditions (such as low back pain, osteoarthritis pain) that may confound the assessment or self-evaluation of the pain due to DPN.
7. Clinically significant unstable diabetes mellitus, or unstable hepatic, respiratory, or hematologic illnesses, unstable cardiovascular disease (including a myocardial infarction in the 3 months prior to V1), or symptomatic (painful) peripheral vascular disease.
8. Amputations due to diabetic complications of body parts other than toes.
9. History or current evidence of any condition that could lead to impaired absorption of vitamin B12 (pernicious anemia, chronic gastritis of any cause, surgery such as gastrectomy or gastric bypass surgery, etc.)
10. Untreated hypothyroidism, chronic hepatitis B, hepatitis B within the past 3 months, or known HIV infection.
11. Have had a malignancy other than basal cell carcinoma or carcinoma in situ of the cervix within the past 5 years.
12. Have creatinine clearance (CLcr) < 60 mL/min (estimated prior to Visit 2 from serum creatinine obtained at Visit 1, body weight, age, and gender using the Cockcroft and Gault equation). Subjects who have an estimated CLcr <60 mL/min by this screening method may have their CLcr measured, at the investigator’s discretion, with a 24 hour urine collection performed at the central laboratory. If this 24 hour urine CLcr is ≥60 mL/min, the subject is not excluded on the basis of this criterion.
13. Clinically significant abnormal electrocardiogram (ECG) by the Investigators' discretion.
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
15. Use of prohibited concomitant meds which cannot be safely washed out prior to study participation. These medications include but are not limit to: those used to relieve neuropathic pain (other than underlying NSAIDs); antiepileptics (including gabapentin); antidepressants.
Note: SSRIs for managing depression and/or anxiety are allowed if stable >30 days and can be maintained without change during the study.
16. Currently receiving pregabalin or opioids (other than tramadol) for painful DPN.
17. Participation in other studies in the 30 days before the current study begins and/or during study participation.
18. Any subject considered at risk of suicide or self harm based on investigator judgment and/or the details of a risk assessment, as specified in Section 7.
19. Abuse of illicit drugs or alcohol within the last 2 years.
20. Unlikely to be able to comply with the protocol because of social or other reasons.
21. Subjects who are investigational staff members or relatives of those site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Endpoint mean pain score, based on the mean of the last 7 daily pain numeric rating scale (NRS) scores from the daily pain diaries while receiving study medication in each treatment period (eg, daily pain diary (0-10 numeric rating scale)). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Reduction in DPN pain, as from the daily pain diaries while receiving study medication in each treatment period (V2-V6 & V7-V11)
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E.5.2 | Secondary end point(s) |
• Proportions of ≥30% and ≥50% pain responders using NRS scores from the daily pain diary (Pain Diary).
• Patient Global Impression of Change assessed at the end of Period 1 (PGIC).
• Daily Sleep Interference Rating Scale (Sleep Diary).
• Quality of life using Norfolk Quality of Life Questionnaire – Diabetic Neuropathy (QoL-DN).
• European Quality of Life in 5 Dimensions (EQ- 5D).
• Pain severity and impact using the Brief Pain Inventory – short form (BPI-sf).
• Anxiety and depression using the Hospital Anxiety and Depression Scale (HADS).
Exploratory Efficacy Endpoints
• Patient Global Impression of Change assessed at the end of Period 2 (PGIC).
• Patient Static Global Assessment (PSGA).
• The relationship between PGIC and PSGA. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Responder rate based on a 30% and 50% improvement in mean pain response (from daily pain diary) (V2-V6 & V7-V11);
• Brief Pain Inventory-short form (BPI-sf) - V2, V6/ET & V11/ET;
• Norfolk Quality of Life Questionnaire for Diabetic Neuropathy (QOL-DN) modified with 2 week recall (V2, V6/ET & V11/ET);
• Patient Global Impression of Change (PGIC), assessed at the end of period 1 compared to the start of treatment (V6/ET & V11/ET);
• Sleep Interference Rating Scale (daily sleep diary) V1-V12:
• Hospital Anxiety and Depression Scale (HADS) V2, V6/ET & V11/ET
• Euro QoL-5 Dimensions (EQ-5D) V2, V6/ET & V11/ET |
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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 | No |
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 | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Yes |
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 | No |
E.8.1.6 | Cross over | Yes |
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.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 | No |
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 |
Austria |
Czech Republic |
Italy |
South Africa |
Sweden |
United States |
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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 | |
E.8.9.1 | In the Member State concerned days | |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 14 |