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Published on: October 22, 2014
Effects of sapropterin on endothelium-dependent vasodilation in patients with CADASIL: a randomized controlled trial
Renata De Maria1, Jonica Campolo1, Marina Frontali1
1From the CNR Institute of Clinical Physiology, CardioThoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); CNR Institute of Translational Pharmacology, Rome, Italy (M.F.); Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (F.T., C.M., C.T.); Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy (A. Federico, M.T.D., M.L.S.); NEUROFARBA Department, Neuroscience Section, University of Florence, Florence, Italy (D.I., R.V.); Department of Epidemiology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (A.T., C.P.); Department of Neuroscience, Mental Health and Sensory Organs (NESMOS) and Center for Experimental Neurological Therapies, Sant'Andrea Hospital, University of Rome "La Sapienza", Rome, Italy (S.R., F.O.); Neurovascular Treatment Unit, University of Rome "La Sapienza" Rome, Italy (E.P., A. Francia); and Stroke Unit and Neurology, Azienda Ospedaliera Universitaria Careggi, Florence, Italy (L.P., F.P.).CNR Institute of Clinical Physiology, CardioThoracic and Vascular Department, Niguarda Ca' Granda HospitalCNR Institute of Clinical Physiology, CardioThoracic and Vascular Department, Niguarda Ca' Granda Hospital;Department of Medicine, Surgery and Neurosciences, University of Siena.
Insights
Sapropterin, a synthetic tetrahydrobiopterin analog, was tested in patients with Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). The study found sapropterin to be safe but ineffective in improving endothelium-dependent vasodilation in these patients.
Area of Science:
- Neurology
- Vascular Biology
- Pharmacology
Background:
- Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic disorder characterized by vascular abnormalities and recurrent strokes.
- NOTCH3 gene mutations are the cause of CADASIL, leading to impaired function of vascular smooth muscle and endothelial cells.
- Altered vasoreactivity and endothelial dysfunction are key factors in CADASIL progression.
Purpose of the Study:
- To evaluate the efficacy of sapropterin, a tetrahydrobiopterin analog, in improving endothelial function in CADASIL patients.
- To assess whether sapropterin can enhance endothelium-dependent vasodilation, a critical aspect of vascular health.
- To determine the safety and tolerability of sapropterin supplementation in the CADASIL population.
Main Methods:
- A 24-month, multicenter, randomized, double-blind, placebo-controlled trial was conducted.
- Participants aged 30-65 years with CADASIL were randomized to receive either placebo or sapropterin (200-400 mg BID).
- The primary outcome measure was the change in the reactive hyperemia index (RHI) assessed by peripheral arterial tonometry at 24 months.
Main Results:
- The study included 61 patients (32 on sapropterin, 29 on placebo).
- No significant difference in the primary endpoint (change in RHI) was observed between the sapropterin and placebo groups.
- While RHI increased in a higher percentage of patients on sapropterin, this improvement was not statistically associated with the treatment arm after adjusting for covariates. Sapropterin was found to be safe and well-tolerated.
Conclusions:
- Sapropterin supplementation did not significantly improve endothelium-dependent vasodilation in patients with CADASIL.
- The drug demonstrated good safety and tolerability at an average dose of 5 mg/kg/day.
- These findings suggest that targeting nitric oxide synthesis via sapropterin may not be a viable therapeutic strategy for improving vascular function in CADASIL.
Background And Purpose:
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients.
Methods:
In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat.
Results:
The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, -0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively.
Conclusions:
Sapropterin was safe and well-tolerated at the average dose of 5 mg/kg/day, but did not affect endothelium-dependent vasodilation in CADASIL patients.
Clinical Trial Registration Url:
https://www.clinicaltrialsregister.eu. Unique identifier: 2007-004370-55.
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