| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Painful Diabetic Peripheral Neuropathy (DPN) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pain caused by damage to the nerves as a result of diabetes |
|
| 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 | 20.0 |
| 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 |
|
| 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 |
Part 1 (Pilot Arm):
To evaluate the safety and tolerability of MT-8554 to determine the dose level administered in Part 2.
Part 2 (Cross-over Arm):
To evaluate the efficacy of MT-8554 in reducing pain intensity in subjects with painful DPN. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the tolerability and safety of MT-8554 in subjects with painful DPN.
• To investigate the effect of MT-8554 on time to sustained improvement in pain, night-time pain, pain intensity and sleep interference in subjects with painful DPN.
• To evaluate the efficacy of MT-8554 in reducing pain intensity in subjects by phenotype (i.e., preserved small fibre function/non preserved small-fibre function profiles).
• To evaluate the effect of MT-8554 on the Patient Global Impression of Change (PGIC) questionnaire and Clinician Global Impression of Change (CGIC) questionnaire. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent obtained to participate in this study after reading the participant information sheet and informed consent form and after having the opportunity to discuss the study with the Investigator or designee.
2. Male subjects and female subjects aged ≥18 years at Screening.
3. Subjects and partners who agree to use contraception (as defined in the Protocol Section 4.7.1) throughout the study.
4. In the Investigator’s opinion, the subject is able to understand the nature of the study and any risks involved in participation, and willing to cooperate and comply with the Protocol restrictions and requirements.
5. Subjects with diabetes mellitus (type 1 or 2) with distal symmetric chronic sensorimotor painful peripheral neuropathy as confirmed by a score of >2 points on Section B (physical examination) of the Michigan Neuropathy Screening Instrument.
6. A history of pain for at least 6 months and ≤7 years attributed to DPN at the time of Screening.
7. For Part 2 only: A baseline 24-hour daily API score ≥4 and ≤8 in both lower limbs as measured on an 11-point pain intensity NRS. The baseline score is the calculated median of the 24-hour daily API scores during the 7 days prior to randomisation for Treatment Period 1. In Part 2, the subject must record at least 4 assessments of the 24 hour daily API score during the 7-day placebo run-in period in their eDiary. However, subjects who experience a >30% variation in daily API score during Placebo Baseline 1 will be excluded.
8. Subjects willing to withdraw from their neuropathy medications prior to Visit 2 and for the whole duration of the study. Acetaminophen/paracetamol is allowable as rescue medication if dosed at up to 3 g/day, if required for pain relief. Should acetaminophen/ paracetamol provide insufficient relief from pain then use of metamizole in single doses up to 1 g and up to the maximum daily dose of 4 g is allowed. The label restrictions for acetaminophen/paracetamol and metamizole will apply.
9. Diabetes which did not require a change in anti-diabetic therapy in the 2 months prior to Screening.
10. For Part 2 only: Glycosylated haemoglobin (HbA1c) ≤10.5% at Screening.
11. A body mass index (Quetelet index) ranging from 18 to 45 kg/m2 (inclusive) at Screening. |
|
| E.4 | Principal exclusion criteria |
1. Other chronic pain conditions not associated with DPN that may confound the assessment of neuropathic pain. However, the subject will not be excluded if:
• The pain condition is located at a different region of the body (other then lower limbs), and
• The pain intensity of this condition is not greater than the pain intensity of DPN, and
• The subject can assess pain due to DPN independently of their other pain condition.
2. Other causes of neuropathy or lower extremity pain which may include, but not be limited to:
a. Lower extremity pain of any severity caused by: gout, bursitis, or fasciitis.
b. Past medical history or known current medical condition of diffuse peripheral neuropathy caused by alcoholism, malignancy, human immunodeficiency virus (HIV), syphilis, drug abuse, peripheral ischaemia, Vitamin B12 deficiency, monoclonal gammopathy, hypothyroidism, liver disease, chemotherapy or radiation therapy.
c. Focal neuropathy in the lower extremities including nerve entrapment or local trauma.
d. Acute or chronic inflammatory polyradiculopathy.
e. Multiple sclerosis or other conditions associated with central neuropathic pain.
f. Pain associated with distal limb ischaemia including intermittent claudication.
3. Current or known history of complex regional pain syndrome or trigeminal neuralgia.
4. Subjects who have been on pain treatment with strong opioids in the previous year, >4 different drug treatments in the previous year, or a current combination of >3 drugs for neuropathic pain.
5. Use of the following drugs within [x] weeks prior to Visit 2:
a. [12 weeks] Capsaicin.
b. [4 weeks] Lidocaine patch.
c. [2 weeks] Antidepressants, anticonvulsants or mexiletine. Opioids or morphinomimetics. Alpha lipoic acid or Vitamin B supplements.
d. [1 week] Acetylsalicylic acid except up to 325 mg/day post-myocardial infarction or prevention, transient ischaemic attack prophylaxis. Benzodiazepines, other than zolpidem 5 mg used for sleep disorders.
6. Use of non-drug therapies or procedures for the relief of pain of DPN within 1 week prior to Visit 2. Nerve blocks are not to be performed within the last 8 weeks prior to Visit 2.
7. Current diagnosis of active epilepsy or any active seizure disorder requiring chronic therapy with antiepileptic drug(s).
8. Current diabetic foot ulcer.
9. Lower extremity amputations other than toes.
10. History of alcohol, solvent or drug use disorder.
11. For Part 2 only: A change in symptomatology between “preserved small fibre function”, and “non-preserved small fibre function” phenotype from Screening to Baseline Visit, based on QST results.
12. Subjects who have participated in a clinical study of any IMP (other then IMP) within 12 weeks (from last administration) prior to Screening or who are currently participating in another clinical study.
13. Pregnancy, lactation or a positive serum beta human chorionic gonadotropin (hCG) level, or intention to become pregnant or to breast feed from the Screening Visit until 3 months after the last dose of IMP.
14. Clinically significant or uncontrolled endocrine, thyroid, hepatic (including Gilbert’s syndrome), neurological (other than neuropathy), respiratory, gastrointestinal, dermatological, renal, cardiovascular disease, psychiatric/psychotic illness disorder (including major depressive disorder) or any other condition that could interfere with the objectives of the study or the safety of the subject.
15. Unstable or uncontrolled diabetes.
16. Presence or history of cancer within the past 2 years with the exception of adequately treated localised basal cell skin cancer or in situ uterine cervical cancer.
17. Subjects with a history of vasomotor symptoms within the past 2 weeks and/or current symptoms.
18. Uncontrolled hypertension at Screening.
19. Use of the following drugs within 1 week prior to Visit 2:
a. Drugs known to be predominantly metabolised by cytochrome P450 (CYP) 2C8.
b. Drugs that are known substrates of CYP3A4, Organic Anion Transporter 3 or P glycoprotein.
20. Subjects with aspartate aminotransferase, alanine aminotransferase ≥2 × upper limit of normal at Screening.
21. Subjects with an estimated glomerular filtration rate (Modification of Diet in Renal Disease formula) <60 mL/min/1.73m2 at Screening.
22. Family history of long or short QT syndrome, hypokalaemia, syncope or Torsades de Pointes.
23. Clinically significant 12-lead electrocardiogram (ECG) abnormalities, including subjects with corrected QT interval using Fridericia’s formula (QTcF) of >450 ms, at Screening confirmed by repeat assessment.
24. Subjects with evidence of acute ischaemia on 12-lead ECG at Screening, Visit 2 (for Part 1), or Visit 3 (for Part 2).
25. Tympanic body temperature on Day 1 that is outside the local reference range, confirmed by repeat assessment.
For a full list of exclusion criteria, please refer to the Protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1 (Pilot Arm):
Safety assessment, treatment emergent adverse events, vital signs (blood pressure, pulse rate, and body temperature), clinical laboratory examinations (including serum potassium and creatinine), 12-lead ECGs, and tolerability (assessed using a questionnaire).
Part 2 (Cross-over Arm):
Change from baseline in the weekly median 24-hour API score (using a NRS) at Week 1 and Week 2. Weekly median 24-hour API score is the median of the 7 pain ratings during the 1-week period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Various timepoints throughout the study. For details, please refer to the Time and Events schedule in Section 5 of the protocol. |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
• Proportion of subjects with a 30% reduction from baseline at Week 1 and Week 2 in weekly median 24-hour API score (using a NRS).
• Proportion of subjects with a 50% reduction from baseline at Week 1 and Week 2 in weekly median 24-hour API score (using a NRS).
• Weekly median night-time API score (using a NRS): night-time is defined as the time between going to bed at night and rising in the morning.
• Weekly median day-time API score (using a NRS): day time is defined as the time between rising in the morning and going to bed at night.
• Weekly median 24-hour worst pain intensity score (using a NRS): worst pain is calculated as the maximum pain experienced by the subject during day-time and night time.
• Change in 24-hour API score from baseline (i.e., median 24-hour API score at baseline) at the end of Weeks 1 and 2.
• Number of subjects who are responders (defined as "much improved" or "very much improved") on the PGIC questionnaire.
• Number of subjects who are responders (defined as "much improved" or "very much improved") on the CGIC questionnaire.
• Time to onset of sustained improvement in the 24-hour API score. Sustained improvement is defined as a reduction of ≥2 points from baseline (i.e., median API score at baseline) for ≥2 consecutive days on the 24-hour daily API score. Time to onset is measured from baseline and calculated as first day of event minus last day of baseline and is expressed in days.
Safety:
• Tolerability (assessed using a questionnaire).
• Incidence and severity of AEs.
• Physical examination.
• Vital signs (blood pressure, pulse rate and body temperature).
• Safety laboratory parameters (haematology, coagulation, biochemistry and urinalysis).
• 12-lead ECG parameters.
• Continuous glucose monitoring (CGM). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Various timepoints throughout the study. For details, please refer to the Time and Events schedule in Section 5 of the protocol. |
|
| 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 | Yes |
| 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 |
|
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 13 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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