| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Trigeminal neuralgia is a severe neuropathic facial pain that currently can often not be well controlled pharmacologically. The gold standard for medical treatment remains carbamazepine, which may produce severe side effects and numerous drug interactions, or may not be effective. There is a recognized need to find other drugs that will provide pain relief with fewer side effects than carbamazepine, or in such cases where carbamazepine is without effect.
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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 | 10044652 |
| E.1.2 | Term | Trigeminal neuralgia |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The objective of the study is to confirm the efficacy and tolerability of immunomodulation with low dose IVIG in refractory trigeminal neuralgia. |
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| E.2.2 | Secondary objectives of the trial |
| We also expect that this trial can provide a basis for other larger trials both in trigeminal neuralgia and also in other refractory neuropathic pain conditions. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are suitable for consideration for screening and enrollment if they have received a diagnosis of trigeminal neuralgia (TN) according to International Headache Society criteria including both ‘classical TN’, or with features of ‘atypical TN’ (Burchiel 2003) providing they initially presented with ‘classical TN’ (Nurmikko and Eldridge 2001). For clarity, these criteria are listed here:
A. Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, affecting one or more division of the trigeminal nerve and fulfilling criteria B and C
B. Pain has at least one of the following characteristics
1. Intense, sharp, superficial or stabbing
2. Precipitated from trigger areas or by trigger factors
C. Attacks are stereotyped in the individual patient
D. There is no clinically evident neurological deficit
E. Not attributed to another disorder
Patients are suitable if they report a dull, burning pain after the shooting paroxysms which then also disappears (atypical form). In addition, there may be a constant element to the pain, but only if in the judgement of the consultant pain specialists responsible for enrolling the patient this patient has had on initial presentation a credible diagnosis of classical trigeminal neuralgia (without a constant element). In addition, patients are also suitable if they have a neurological deficit which is considered by one of the consultant grade site investigators to have emerged following an interventional procedure aimed to relieve pain from TN. Patients who have had previous successful surgical treatments but who have suffered a recurrence of classical or atypical TN are suitable. Patients on a stable dose of antiepileptic drugs are suitable. Treatment with antiepileptic drugs prior to enrolment will be noted, but prior treatment with antiepileptic drugs other than carbamazepine is not a prerequisite for consideration for screening and enrollment.
Patients fulfilling the above listed suitability criteria may be screened if they
• are willing to participate in the study as evidenced by giving written informed consent and willingness to return to the study site at the intervals specified in the protocol.
• are male or female above 18 years of age.
• are females and there is evidence that they are not pregnant or lactating. A urine pregnancy test will be performed on the day of the first infusion. Confirmation of use of adequate birth control will be required.
• have no physical condition, which, in the opinion of the investigator, is unstable or would otherwise prevent the patient from completing the study.
• have sufficient cognitive function and English language skills or the availability of a translator to complete questionnaires, keep a daily diary, use an electronic diary, and communicate verbally with the nursing staff. English language skills or the availability of a translator are required because not all the questionnaires have been translated or validated in other languages.
• are receiving a stable dose of an antiepileptic drug, with adequate pain control, but experience a poor side-effect profile, as judged by both the patient (documented by ticking ‘non acceptable’ to a question: ‘do you consider side effects from your medication taken for pain acceptable – non acceptable) and the consultant-grade site investigator.
Patients may be enrolled if they
• have an average 24h pain severity of >4 on a numeric scale of 0-10 during the seven day screening period and at least moderate on a scale none-mild-moderate-severe. During an initial patient-education module the use of these scales will be explained in detail. For example if patients only experience attacks, without any constant element, then the mean intensity of painful attacks will be noted. If the pain level when taking medication is lower, but adverse events associated with that medication are considered not acceptable (see above), then the respective medication would first be reduced, and a stable pain level in accordance with the entry criteria be achieved for at least four consecutive
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| E.4 | Principal exclusion criteria |
All patients have their serum IgA level tested and if less than half the normal value then the patient may be excluded. In patients with an absence of IgA or with severe IgA deficiency, it is believed that IVIG administration will result in the formation of immune complexes between IgA antibodies present in the drug and traces of preformed anti IgA in patients (Kazatchkine and Kaveri 2001). Pregnant or lactating females are excluded from the study. Patients with progressive renal failure, bedridden patients and any patient requiring IVIG for another disorder are excluded. Treatment will be deferred in patients with an infection such as cold, flu or infected pressure sores until the infection has resolved, because previous experience has shown a reduced analgesic effect of IVIG in these cases. Further, patients are excluded, should they
• have evidence of significant organic disease on history or physical examination, which may be severe enough to prevent the patient from being able to complete the study.
• suffer from another severe chronic pain syndrome which may in the judgement of the site investigator hinder the appropriate assessment of pain from trigeminal neuralgia
• have a history of or are currently abusing alcohol or drugs.
• take carbamazepine plus other medication that may interact with carbamazepine , e.g. warfarin
• have a psychological/psychiatric disorder as identified by a pre-study entry psychiatric assessment.
• be unwilling to complete daily diaries.
For the following patients suitability for participation needs to be discussed with a specialist consultant: patients with compensated renal failure, patients suffering from epilepsy, patients with a history of stroke or myocardial infarction and patients with a known procoagulatory or blood-hyperviscosity disorder. It is expected that, following discussion with the respective consultant usually these patients can participate, but the maximal infusion rate will be reduced to half the usual infusion rate in most patients with renal failure or a history of stroke or myocardial infarction.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure is the number of patients remaining in the trial at day 14 because they experience significant pain relief. |
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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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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.8.3 |
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 | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | Information not present in EudraCT |
| 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
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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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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