Long-Term Study of Nitisinone to Treat Alkaptonuria
Mots clés
Abstrait
La description
Alkaptonuria is a rare metabolic disease in which homogentisic acid (HGA), an intermediary metabolite in tyrosine catabolism, accumulates due to deficiency of the enzyme homogentisic acid oxidase. Patients with alkaptonuria exhibit homogentisic aciduria and ochronosis, or dark pigmentation of various tissues due to binding of HGA and its oxidized metabolites. The ochronosis results in debilitating destruction of cartilage, arthritis, lumbosacral ankylosis, limitation of motion, and bone deterioration in later life. No effective therapy exists for alkaptonuria. However, a compound named 2-(2-nitro-4-trifluoromethylbenzoyl) - 1, 3-cyclohexanedione (nitisinone, NTBC, Orfadin) inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme that produces HGA. Nitisinone, at doses of approximately 1 mg/kg/day, has proven safe and effective in tyrosinemia type I, which causes fatal liver disease in infants and children. Under protocol 97-HG-0201, we treated 9 alkaptonuria patients with nitisinone; for the 7 who received 1.05 mg twice daily, the HA fell from 4.0 plus or minus 1.8 g/24h to 0.2 plus or minus 0.2 g/24h (normal 0.028 plus or minus 0.015 g/24h, n=10). Plasma tyrosine levels rose from 67 plus or minus 18 micro M to 760 plus or minus 181 micro M. The current protocol (05-HG-0076) is a randomized, controlled clinical trial to determine if nitisinone (2 mg daily) is beneficial for the joint symptoms of alkaptonuira. Patients are examined at the NIH Clinical Research Center every 4 months for 3 years. Hip joint range of motion serves as the primary outcome parameter, and nitisinone (Orfadin) is provided by Swedish Orphan International through an IND obtained by William A. Gahl. Forty patients (20 with nitisinone treatment and 20 untreated) have been enrolled for at least 16 months, and an interim analysis shows promising results. Serious adverse events in patients on nitisinone have included a death from myocardial infarction, keratopathy, and elevated liver function tests related to gallstones.
Rendez-vous
| Dernière vérification: | 11/30/2010 |
| Première soumission: | 04/06/2005 |
| Inscription estimée soumise: | 04/06/2005 |
| Première publication: | 04/07/2005 |
| Dernière mise à jour soumise: | 12/19/2010 |
| Dernière mise à jour publiée: | 01/18/2011 |
| Date des premiers résultats soumis: | 12/19/2010 |
| Date de la première soumission des résultats du CQ: | 12/19/2010 |
| Date des premiers résultats publiés: | 01/18/2011 |
| Date de début réelle de l'étude: | 12/31/2004 |
| Date d'achèvement primaire estimée: | 03/31/2009 |
| Date estimée d'achèvement de l'étude: | 03/31/2009 |
Condition ou maladie
Intervention / traitement
Drug: Nitisinone-treated
Phase
Groupes d'armes
| Bras | Intervention / traitement |
|---|---|
| No Intervention: Control No treatment | |
| Experimental: Nitisinone-treated Subjects received nitisinone 2 mg orally, once daily. | Drug: Nitisinone-treated Treatment |
Critère d'éligibilité
| Âges éligibles aux études | 30 Years À 30 Years |
| Sexes éligibles à l'étude | All |
| Accepte les bénévoles en santé | Oui |
| Critères | - INCLUSION CRITERIA: - Age 30-80 years, either gender - Diagnosis of alkaptonuria based upon urinary HGA excretion greater than 0.4 g/24h - At least one hip joint remaining - Some evidence of hip involvement, e.g., pain or decreased range of motion - Ability to travel to the NIH Clinical Research Center for admissions - Ability to consent - Availability of local medical follow-up EXCLUSION CRITERIA: - Age less than 30 or greater than 80 - Non-alkaptonuria causes of ochronosis - Bilateral hip joint replacement - Keratopathy - Contact lenses - Uncontrolled glaucoma - History of myocardial infarction - History of emphysema or pulmonary insufficiency (Forced vital capacity less than 70%) - Psychiatric illness or neurological disease that interferes with compliance or communication with health care personnel - Current malignancy - Open skin lesions - Dietary habits or use of homeopathic therapies that interfere with tyrosine catabolism. The diet must be reasonably balanced, as determined by a dietician. - Uncontrolled hypertension (blood pressure greater than 180 systolic or greater than 95 diastolic) - History of extreme alcohol abuse or sever liver disease - Liver greater than 3 cm below the right costal margin - Electrocardiogram changes indicative of myocardial infarction, arrhythmia, tachycardia, bradycardia, left bundle branch block - Chest radiographic abnormalities, including an infiltrate, mass, congestive heart failure, embolism, atelectasis - Serum postassium less than 3. 0 mEq/L - Serum creatinine greater than 2.0 mg/dL - SGPT greater than 41 U/L or SGOT greater than 34 U/L - CK greater than 500 U/L - Hemoglobin less than 10.0 g/dL - Platelets less than 100 k/mm(3) - WBC less than 3.0 k/microL - T4 greater than 15 microg/dL - T4 less than 4 microg/dL - ESR greater than 100 mm/h - Plasma tyrosine greater than 150 microM |
Résultat
Mesures des résultats primaires
1. Change in Total ROM Worse Hip. [Measured at baseline and at 36 months]
Mesures des résultats secondaires
1. Change in Schober's Test [Measured at baseline and at 36 months]
2. Change in Functional Reach Assessment [Measured at baseline and at 36 months]
3. Change in Timed Get up and go [Measured at baseline and at 36 months]
4. Change in 6 Minute Walk Test (6MWT) [Measured at baseline and at 36 months]
