| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pain due to diabetic polyneuropathy. |
|
| E.1.1.1 | Medical condition in easily understood language |
| pain due to diabetic nerve damages |
|
| 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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012685 |
| E.1.2 | Term | Diabetic polyneuropathy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 analgesic efficacy of fixed doses of 25 µg, 75 µg, and 200 µg GRT6005 once daily compared to placebo in subjects with moderate to severe pain due to diabetic polyneuropathy. |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the safety and tolerability of fixed doses of 25 µg, 75 µg and 200 µg GRT6005 once daily compared to placebo in subjects with moderate to severe pain due to diabetic polyneuropathy.
-To explore the relationship between exposure to GRT6005 and analgesic efficacy and tolerability.
-To describe multiple dose kinetics of GRT6005 over 4 weeks in subjects with pain due to DPN.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects must have signed an informed consent form.
2. Male or female subjects aged 18 years to 75 years inclusive at the Enrollment Visit.
3. All subjects must have type 1 or type 2 diabetes mellitus and must have a documented clinical diagnosis of painful DPN with symptoms and signs for at least 3 months and pain present at the Enrollment Visit.
4. The investigator considers the subject’s blood glucose to be controlled by a diet, oral anti-hyperglycemic medication, and/or insulin for at least 3 months prior to enrolling in the trial. This control should be documented.
Hemoglobin (HbA1C) should not be greater than 11.0% at the Enrollment Visit.
For Germany only: Hemoglobin (HbA1C) should not be greater than 9.5% at the Enrollment Visit.
5. Subjects must be using medically acceptable and highly effective methods of birth control:
For women of childbearing potential: A medically acceptable and highly effective method of birth control is defined as any form of contraception with a low failure rate defined as <1% per year.
For example:
- Hormonal contraceptives for at least 2 months prior to the Enrollment Visit and until at least 4 weeks after the Final Visit.
- An intra-uterine device. Additional barrier contraception must be used by the partner for the duration of the trial, defined as from the time of the Enrollment Visit until 4 weeks after the Final Visit. Women of non-childbearing potential may be included if surgically sterile (i.e., after hysterectomy) or post-menopausal for
at least 2 years.
For men: Males have to use barrier contraception (condom) during sexual intercourse and not have sex with women who are pregnant or lactating from the first administration of IMP until 4 weeks after the Final Visit. The male subject has to take care that the female sexual partner uses at least 1 additional method of
contraception with a low failure rate defined as <1% per year (e.g., oral contraceptives for at least 2 months prior to the Enrollment Visit) during this time frame. A double-barrier method should be supplemented by the use of
spermicidal agents.
6. Women of childbearing potential must have a negative urine β-human chorionic gonadotropin (β-hCG) pregnancy test at the Enrollment Visit (Visit 1) and at the Baseline Visit (Visit 3).
7. Subjects must be on stable analgesic medications for their condition with regular intake for at least 3 months prior to the Enrollment Visit according to their medical history and must be dissatisfied with their current analgesic treatment in terms of
efficacy and/or tolerability prior to signing the informed consent form.
8. A daily average pain intensity score ≥4 on the 11-point numeric rating scale (NRS) during the last 3 days prior to the Baseline Visit without intake of rescue medication, during which a subject completed at least 5 of 6 possible pain intensity assessments of these 3 days. |
|
| E.4 | Principal exclusion criteria |
General:
1. Concurrent participation in another trial, or within 30 days before the Enrollment Visit of this trial.
2. Previous participation in this or other trials with GRT6005 (unless enrollment failure due to technical reason).
3. Previous or current alcohol or drug abuse according to the investigator’s judgment, based on subject’s history, physical examination, or the result of the drug test at the Enrollment Visit or at the Baseline Visit.
4. Previous or current opioid dependency, based on subject’s history, physical examination, or the result of the drug test at the Enrollment Visit or at the Baseline Visit.
5. Female subjects who are breastfeeding.
6. Known or suspected of not being able to comply with the protocol and with the use of the IMP.
7. Any clinically significant disease that in the investigator's opinion may affect efficacy or safety assessments or may compromise the subject’s safety during trial participation, such as significant pulmonary, gastrointestinal, endocrine, metabolic, neurological, or psychiatric disorders (e.g., major depression and psychosis).
8. Employees of the investigator, trial site, or sponsor with direct involvement in the proposed trial or other trials under the direction of that investigator, trial site, or sponsor, as well as family members of employees or the investigator.
9. Subjects with impaired hepatic functionality/cellular integrity determined by bilirubin greater than 2.0 mg/dL and albumin lower than 2.8 g/dL or increased transaminases with alanine aminotransferase or aspartate aminotransferase greater than 3 times the upper limit of normal at the Enrollment or the Prebaseline
Visit.
10. History of chronic hepatitis B or C, or human immunodeficiency virus infection, or presence of acute hepatitis A, B, or C within the past 3 months.
11. Subjects with impaired renal function. Creatinine clearance less than 60 mL/min at the Enrollment Visit or the Pre-baseline Visit (calculated from the Cockcroft-Gault formula).
12. Any chronic gastrointestinal disease (e.g., celiac disease or colitis ulcerosa) or previous major abdominal surgery (e.g., Billroth procedure or enteroanastomosis) that might affect drug absorption or excretion.
13. Significant cardiac disease (e.g., unstable angina pectoris, angina pectoris Canadian Cardiovascular Society Class III-IV, acute myocardial infarction within the last 3 months, cardiac insufficiency New York Heart Association Class III-IV).
14. Presence of risk factors for Torsade de Pointes (e.g., heart failure, hypokalemia, bradycardia).
15. Marked prolongation of QTc >470 ms at the Enrollment Visit or the Pre-baseline Visit.
16. History of seizure disorder and/or epilepsy or any condition associated with a significant risk for seizure disorder or epilepsy at the Enrollment Visit at the discretion of the investigator.
17. History or presence of malignancy within the past 2 years, with the exception of curative treated subjects or subjects being in remission of cancer for at least 2 years and not requiring treatment.
Trial specific:
18. Any scheduled surgery or painful procedure during the course of the trial.
19. Severe or extensive diabetic ulcers or amputations (more than 2 toes) of the limbs or Charcot joints.
20. Clinically relevant history of hypersensitivity, allergy, or contraindications to any of the IMP’s excipients as well as to opioids or paracetamol.
21. Significant vascular disease (e.g., peripheral occlusive arterial disease, Fontaine Class III–IV; venous insufficiency, postthrombotic syndrome, Stage III/IV).
22. Presence of conditions other than painful DPN that could contribute to pain or confound the assessment of self-evaluation of pain, for instance fibromyalgia, complex regional pain syndrome, phantom pain, significant skin conditions such as
abscesses, significant osteoarthritis, low back pain, inflammation (e.g., rheumatoid arthritis, ankylosing spondylitis), and vasculitis.
23. Subjects whose body weight is lower than 50 kg.
24. Conditions that require treatment with prohibited medication (see Section “Concomitant treatments”). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in the pain intensity scores (on an 11-point NRS) during the last week of the 4-week Treatment Period. The pain intensity scores will be evaluated as the mean of the 2 average pain intensity assessments over the last 12 hours. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Complete last week of treatment |
|
| E.5.2 | Secondary end point(s) |
•Assessment of different responder definitions (rates of 10% to 90% improvement of pain intensity score from baseline) at the treatment visits for Week 1, Week 2, and Week 3, and at the Final Visit.
•Change from baseline in the pain intensity scores (on an 11-point NRS) during the entire 4-week Treatment Period.
•Change from baseline in the pain intensity scores (on an 11-point NRS) in the first, second, and third week of the 4-week Treatment Period and in the last 24 hours before the Followup Visit.
•Weekly mean of current pain intensity (on an 11-point NRS) in the morning and in the evening.
Quantitative sensory testing (with a selection of tests, i.e., cotton swab testing, brushevoked pain): changes from Baseline to the treatment visit of Week 1 and to the Final Visit.
• NPS: change from baseline to the treatment visit of Week 1 and to the Final Visit.
• SF-BPI scores: change from baseline to the Treatment Visit Week 1 and to the Final Visit.
• PGIC and CGIC at the treatment visit for Week 1 and at the Final Visit.
• LSEQ at the treatment visit for Week 1 and at the Final Visit.
• Quality of Life Index – SF-12: Changes from the Baseline Visit to the treatment visit for Week 1 and to the Final Visit.
• EQ–5D: Changes from the Baseline Visit (Visit 3) to Visit 7.
• Assessment of rescue medication usage during the Treatment Period.
Safety and tolerability
• Frequency of AEs and percentage of subjects discontinuing the trial due to AEs and drugrelated AEs.
• Time to overall withdrawal and time to withdrawal for specific reasons.
Endpoints of specific interest
• Evaluation of plasma concentration of GRT6005 throughout the Treatment and Follow-up Period. Samples will be taken according to Section 2.2 (schedule of events).
• Assessment of potential withdrawal symptoms using COWS at the Follow-up Visit. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Different responder definitions:V4, V5, V6, V7.Change from baseline in pain intensity scores:EntireTreatmentPeriod.Change from baseline in pain intensity scores:week 1,2,3 of Treatment and last 24 hours before Followup Visit. Weekly mean of current pain intensity:Each morning + evening. Quantitative sensory testing:V3, V4, V7. NPS:V3, V4, V7. SF-BPI:V3, V4, V7. PGIC and CGIC:V3, V4, V7. SF-12:V3, V4, V7. EQ–5D:V3, V4, V7. Rescue medication usage:EntireTreatmentPeriod. Frequency AEs + percentage of subjects discontinuing the trial due to AEs and drugrelated AEs:Entiretime. Time to overall withdrawal and time to withdrawal for specific reasons:Entiretime. Evaluation of plasma concentration of GRT6005:At Treatment and Follow-up Period. Samples see Protocol section 2.2. COWS: V8. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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