E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Skin-biopsy proven small fiber neuropathy without an underlying cause |
Huidbiopt bewezen dunnevezelneuropathie zonder bekende onderliggende oorzaak. |
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E.1.1.1 | Medical condition in easily understood language |
Skin-biopsy proven small fiber neuropathy without an underlying cause |
Huidbiopt bewezen dunnevezelneuropathie zonder bekende onderliggende oorzaak. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
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 IVIg treatment (4 courses of treatment, 3 weeks apart) compared to placebo by assessing changes on the mean weekly level of peak pain intensity (PI-NRS) compared to baseline scores. |
Evaluatie van de effectiviteit van IVIG behandeling (4 behandelingen, 3 weken ertussen) in vergelijking met een placebo, door the kijken naar het verschil in het gemiddelde wekelijkse niveau van de maximale pijn intensiteit (PI-NRS) in vergelijking met de baseline. |
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E.2.2 | Secondary objectives of the trial |
Corneal confocal microscopy, pain intensity, pain qualities, and other SFN related complaints, daily and social functioning, as well as quality of life will be assessed. Safety: adverse events, vital signs and laboratory values outside the normal range |
Cornea confocale microscopie, pijnintensiteit, pijnkwaliteit en andere DVN gerelateerde klachten, dagelijks en sociaal functioneren en de kwaliteit van leven. Veiligheid: advese events, vitale kenmerken en laboratorium onderzoek buiten de normaalwaarden. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• 18 years or older. • Skin-biopsy proven idiopathic SFN or idiopathic painful neuropathy with predominantly SFN pattern • Pain intensity rated ≥ 5 on the PI-NRS (maximum pain) or on the neuropathic pain scale,36,37 question number 1 for at least 12 weeks before the study as declared by each patient to the best of their knowledge; if available, medical records of each patient will be consulted on the reported pain intensity. • Each subject will receive an information leaflet and an informed consent form. Subjects must give informed consent by signing and dating prior to study entry. • Eligible patients must be willing to complete all study-related activities and examination required by the protocol
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E.4 | Principal exclusion criteria |
• Are unable or unwilling to provide written informed consent. • Have predominant clinical picture of large nerve fiber involvement (i.e., weakness, loss of vibration sense, hypo-/areflexia). • Had treatment with IVIg or any other immunomodulatory/immunosuppressive agents (e.g., steroids) within the last 12 weeks prior to the date of informed consent. • Have an underlying cause of SFN (diabetes, SCN9A/10A/11A mutations, hypothyroidism, renal failure, vitamin B12 deficiency, monoclonal gammopathy, alcohol abuse (more than 5 IU/day), malignancies, drugs that cause neuropathy (e.g. chemotherapy, amiodarone, propafenone)). • Have a history of anaphylaxis or severe systemic response to immunoglobulin or with a blood product. • Have cardiac insufficiency (NYHA III/IV), cardiomyopathy, significant cardiac dysrhythmia requiring treatment, unstable or advanced ischemic heart disease, or history of congestive heart failure, severe hypertension (diastolic blood pressure >120 mmHg or systolic >170 mmHg). • Are females who are pregnant, breast-feeding, or if of childbearing potential, or unwilling to practice adequate contraception throughout the study. • Have known hyperviscosity. • Have a history of renal insufficiency or high serum creatinine levels (MDRD <30). • Have known selective IgA deficiency. • Have conditions whose symptoms and effects could alter protein catabolism and/or IgG utilization (e.g. protein-losing enteropathies, nephrotic syndrome). • Have a known hypercoagulable state. • Are mentally challenged adult subjects unable to give independent informed consent. • The use of pain (analgesic/anti-neuropathic) medication is allowed, but only if dosages are remained unchanged for at least 30 days prior to randomization. A change in dosage of these drugs will not be allowed throughout the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Comparison of the percentage of responder subjects between the two treatment groups from the first randomization during 12 weeks. A patient withdrawing from the study will be recorded as treatment failure for their randomization arm. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
During the complete length of the study (12 weeks) |
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E.5.2 | Secondary end point(s) |
• The daily pain intensity (defined as the mean pain experienced during the day: from waking up to 6 pm), the nocturnal pain intensity (6 pm until waking up), and the average of these two will also be assessed using the PI-NRS, twice a week.51 • Change of painful symptoms will be compared to baseline using the patients’ global impression of change (PGIC) on a 7-point Likert scale. Subsequent scores of the PGIC are 1) “worse than ever”; 2) “much worse”; 3) “little worse”; 4) “no change”; 5)”little improved”; 6) “much improved”; 7)”completely resolved”. “Completely resolved” and “much improved” are considered as a relevant improvement. Clinically relevant pain reduction on PGIC for pain will be defined as score 6 (“much improved”) or 7 (“completely resolved”).52,53 • The Rasch-transformed 13 items SFN symptoms inventory questionnaire (RT-SFN-SIQ) highlights sensory symptoms, pain and autonomic complaints.16 Differences between the two arms will be examined using its score obtained after interval transformation using the Rasch method.54,55 • The amount of pain medication used during the trial will be registered in the pain diary and will be used to compare the impact of the treatment versus placebo arms. • Patients will be requested to register (in a pain diary) the frequency and duration of occurrence and duration (in hours)) of non-medical rescue activities as well, such as using cooling/heating and forced resting. • Pain relief will also be captured on a daily basis using a 5-point Likert-scale: 0: no relief, 1: slight, 2: moderate, 3: good, and 4: complete relief. This is according to the IMMPACT recommendations.53 • The neuropathic pain scale (NPS) will also be recorded to determine the various pain qualities.37 • Daily Sleep Interference Scale (DSIS) will also be completed by subject twice a week on waking (11-point numerical scale ranging from 0 (pain does not interfere with sleep) to 10 (pain completely interferes with sleep)). • Rasch-built Overall disability Outcome Scale specifically designed for SFN (SFN-RODS): the SFN-RODS is the only clinimetrically evaluated scale at the activity and participation level for assessing outcome in this disorder. Its incorporation will be providing data on its possible responsiveness.56 • The Short Form 36 Health Survey (SF-36) is a generic quality of life measure.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During the complete length of the study (12 weeks) |
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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) | 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 | 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 | 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.8.5 | 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 | 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
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The subject is finished with the trial after 6 months. We will include 60 patients. |
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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 | |
E.8.9.1 | In the Member State concerned days | |