The Effect of Diflunisal on Familial Transthyretin Amyloidosis

Study Overview
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Brief Summary
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An ongoing trial of diflunisal has been closed for enrollment, thus, patients suitable for the study can no longer participate or receive treatment by diflunisal; and patients, who have participated in the trial can not continue their treatment. The investigators want to continue to monitor the effect of the drug on transthyretin (TTR) amyloidosis in an open label observational study. Primary endpoint will be a composite score of the manifestations of the disease (Kumamoto scale) and secondary end points will be measurements of neurological impairment, heart involvement and nutritional status.

Detailed Description
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Duration of treatment in this study is dependent of the results from the ongoing IND 68092-study, which are planned to be presented 2013.

Official Title
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The Effect of Diflunisal on Familial Transthyretin Amyloidosis: An Open Label Extension Study of the Diflunisal Trial (IND 68092), and an Open Label Observational Study on Previously Untreated Patients With Familial Transthyretin Amyloidosis.

Conditions
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Amyloidosis

Intervention / Treatment
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* Drug: Diflunisal


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy and genetically proven systemic transthyretin amyloidosis caused by a TTR gene mutation. The amyloid shall be proven to be of transthyretin type, and the fibril composition settled. Age ≥ 18 years. Negative pregnancy test and contraception for sexually active women of child bearing potential. Exclusion Criteria: Concomitant use of non-study non-steroidal anti-inflammatory drugs (NSAIDs) Heart failure with symptoms at daily activities (NYHA class ≥III) Renal insufficiency (creatinine clearance < 30 ml calculated from the Cockcroft-Gault formula) Active non-haemorrhoidal bleeding within the last 18 month. Non-treated peptic ulcer disease. Anticoagulation therapy, low dose ASA permitted. Non-steroidal or aspirin allergy/hypersensitivity Thrombocytopenia (< 100,000 platelets/mm3) Inability or unwillingness of subject to give written informed consent By the investigator regarded as unable to follow the study guidelines and scheduled controls.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Diflunisal|Film-coated tablet, 250 mg twice daily, orally for approximately 2 years|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the Kumamoto scale | Composite score of the manifestations of the disease (Kumamoto Scale). Results at enrollment will be compared to results at 12 months and annual follow-ups. | Enrollment, 12 month and annual follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in modified body mass index (mBMI) | Changes in nutritional status measured by mBMI.Results at enrollment will be compared to results at 12 months and annual follow-ups. | Enrollment, 12 month and annual follow-up | 
| Changes in paraneoplastic neurological disorders (PND) scale | Neurological impairment measured by the PND-score. Results at enrollment will be compared to results at 12 months and annual follow-ups. | Enrollment, 12 month and annual follow-up | 
| Changes in cardiac function | Cardiac impairment is measure by echocardiographic measurement of septal thickness and by proBNP in blood samples. Results at enrollment will be compared to results during the study and annual follow-ups. | Enrollment, 1 month, 2 month, 3 month, 6 month, 9 month 12 month, 18 month and annual follow-up | 
| Safety follow-up Blood Work | To follow-up the patient safety during the study and follow-up the blood samples for (B-Hb), blood platelets, s-creatinine, liver enzymes [aspartate transaminase (ASAT),alanine aminotransferase (ALAT), s-bilirubin and alkaline phosphatase (ALP)],serum proBNP (S-proBNP) are drawn. Results at enrollment will be compares to results during study and every 6-month follow-ups. | 1 month, 3 month, 6 month, 9 month, 12 month and follow-up every 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyloidosis, Transthyretin, Neuropathies, Diflunisal, Familial