E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054095 |
E.1.2 | Term | Neuropathic pain |
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 |
We will examine whether ivabradine reduces the intensity of sensitisation induced by capsaicin. Application of capsaicin cream to the skin causes a reddening of the skin, and an increased sensitivity within the area the cream is applied (the primary hyperalgesia area) and in surrounding areas (the secondary hyperalgesia area). Changes in sensitivity can be assessed using quantitative sensory testing (QST). This will be an enriched population study, meaning that we will only include participants who respond to capsaicin. This will be determined at the screening visit.
The principle research objective is to investigate whether ivabradine reduces the area of secondary punctate mechanical hyperalgesia induced by capsaicin (a change in normal sensation to a von Frey hair or pin prick stimulator). |
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E.2.2 | Secondary objectives of the trial |
The secondary research objectives will be to determine the effect of ivabradine on secondary hyperalgesia using a variety of other thresholds measured using quantitative sensory testing (QST).
The intensity of capsaicin-induced flare will also be assessed using manual tracing, infrared thermography, or laser Doppler imaging.
In the primary area we will assess the warm sensation threshold (WST) and the heat pain threshold (HPT). Other thresholds will be determined such as mechanical pain thresholds (MPT) using a weighted hair called a von Frey hair or a pinprick stimulator to apply increasing forces. Thermal and mechanical hyperalgesia will be determined as the change in threshold from baseline to post-capsaicin application, and compared between treatment arms.
We will map the area of sensitivity as the area in which volunteers feel changes in normal sensation to light stroking with a cotton bud, soft brush or air puff (known as the area of mechanical allodynia).
We will |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Volunteers who have given written informed consent to participate - Volunteers who can communicate fluently in English - Male or female - Aged 18-64 years - Absence of any chronic pain medicine - Volunteers in good general health, including a body mass index (BMI) in the range of 19-35 - Volunteers with a normal resting 12-lead standard ECG including (measured for 1 minute on lead D2): normal sinus rhythm; 60 bpm ≤ HR on resting ECG; PR interval ≤ 210ms; QTcB ≤ 430ms for men and ≤ 450ms for women; QRS duration ≤ 120ms; the results of ECG recordings will be included in the CRF - Women of child bearing potential must use hormonal based contraception for the duration of the trial and 1 week following the end of their trial participation |
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E.4 | Principal exclusion criteria |
- Volunteers with 1 arm - Pre-existing pain on either forearm - Previous surgery or tattoo on either forearm - History of disease associated with neuropathy - Volunteers who are allergic to ivabradine or capsaicin - History of personal or familial Long QT Syndrome - History of cardiac dysrhythmia - Use of CYP3A4 inhibitors such as ketoconazole, itraconazole, macrolide antibiotics and the anti-retrovirals nelfinavir, nefazodone and ritonavir. - Use of CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin or St John’s Wort etc.) - Use of QT interval prolonging medicinal products (e.g. quinidine, disopyramide or pimozide etc.) - Volunteers with any rash or broken skin on the arm where the capsaicin will be applied - Volunteers with lactose intolerance, as the placebo and ivabradine tablets contain lactose - Volunteers with a resting heart rate of 59 beats per minute or less at screening - Volunteers who are pregnant or breast feeding - Female volunteers of childbearing potential who refuse to use hormonal contraceptive measures for the duration of the trial as listed in section 11.5 of the protocol - Male volunteers who refuse to use adequate contraceptive measures for the duration of the trial as listed in section 11.5 of the protocol - Volunteers who have an underlying medical condition such as migraine or epilepsy which may affect the trial findings - Volunteers who smoke (≥5 cigarettes/day), take recreational drugs or consume more than the recommended allowance of alcohol units per week (21 units per week for males and 14 units per week for females) - Participants who are not willing to abstain from drinking beverages containing quinine, caffeine and/or xanthine for 24 hours prior to the trial visit - Volunteers who produce a positive result in a urine screen for drugs of abuse or who are known or suspected to be drug-dependent (sedatives, hypnotics, tranquilizers or any other addictive agent) - Volunteers who produce a positive result in an alcohol breath test - Volunteers currently participating in any interventional trial, have participated in an interventional trial within 16 weeks of screening or are currently participating in a non-interventional trial which participating in this trial would impact upon - Volunteers who, in the opinion of the PI, have a clinically relevant abnormality or medical history that is deemed to make the participant ineligible because of a safety concern.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the area of punctate mechanical hyperalgesia in capsaicin-responders. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change from baseline value (pre-capsaicin) to post-capsaicin value on the screening capsaicin visit.
Change from baseline value (pre-capsaicin) to post-capsaicin value (taken 1.5 hours following drug/placebo administration on the two trial visits)
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E.5.2 | Secondary end point(s) |
Endpoints will be summarised for all subjects from data obtained during the screening capsaicin session for standard reference values of capsaicin-induced hyperalgesia and comparison between capsaicin responders and non-responders. Endpoints will be summarised and compared between placebo and ivabradine treatment arms for data obtained during the two trial visits.
• Pain score measured using a 100mm visual analogue scale (VAS) • Temperature thresholds in an area of sensitised skin including cold sensation threshold, warm sensation threshold, heat pain threshold and cold pain threshold. Thermal hyperalgesia will be determined as the change in threshold from baseline to post-capsaicin, and compared between treatment arms. • Mechanical thresholds in an area of sensitised skin including mechanical pain threshold. The magnitude of mechanical hyperalgesia will be determined as the change in threshold from baseline to post-capsaicin, and compared between treatment arms • The area of mechanical sensitisation determined using light brushing of the skin (tactile allodynia).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Change from baseline value (pre-capsaicin) to post-capsaicin value on the screening capsaicin visit.
Change from baseline value (pre-capsaicin) to post-capsaicin value (taken 1.5 hours following drug/placebo administration on the two trial visits)
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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 | No |
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 | 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 | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
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
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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 | 6 |
E.8.9.1 | In the Member State concerned days | 1 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 1 |