Clinical trials: Curing a critical deficiency in metabolic medicine

Vockley, Jerry; Vockley, Catherine M.Walsh

doi:10.1016/j.ymgme.2009.12.001

Cited by 12 publications

(13 citation statements)

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“…Parenteral OHCbl remains the treatment of choice, and its use has likely decreased the infantile mortality rate in cblC disease considerably (Rosenblatt et al 1997). However, the treatment of cblC disease appears to be based on expert opinion rather than clinical trial results, similar to other rare disorders (Vockley and Vockley 2010). Our review of the literature also showed that the treatment of cblC disease varies significantly, and patients receive different formulations, doses, and routes of administration of cobalamin.…”

Section: Discussionmentioning

confidence: 99%

“…In conclusion, controlled studies are needed to provide appropriate evidence to guide clinical decisions in cblC disease, as has been suggested for other inborn errors of metabolism (Steiner 2005; Vockley and Vockley 2010). These include longitudinal studies to better define the natural history, progression, and factors associated with outcome in cblC disease.…”

Section: Discussionmentioning

confidence: 99%

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Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes

Carrillo-Carrasco

Venditti

2011

J of Inher Metab Disea

103

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Combined methylmalonic acidemia and homocystinuria, cblC type, is stated to be the most common inborn error of intracellular cobalamin metabolism. The disorder can display a wide spectrum of clinical manifestations, spanning the prenatal period through late adulthood. While increased homocysteine concentrations and impaired methyl group metabolism may contribute to disease-related complications, the characteristic macular and retinal degeneration seen in many affected patients appears to be unique to cblC disease. The early detection of cblC disease by newborn screening mandates a careful assessment of therapeutic approaches and provides a new opportunity to improve the outcome of affected patients. The following article reviews the current knowledge on the complications, pathophysiology, and outcome of cblC disease in an effort to better guide clinical practice and future therapeutic trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes

Carrillo-Carrasco

Venditti

2011

J of Inher Metab Disea

103

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“…However, this drawback should not discourage creation of clinical practice recommendations in this group of diseases. As already pointed out by Vockley and coworkers [19],[20] clinical practice recommendations/guidelines may be derived from the integration of evidence-based medicine, review of the literature and consensus from an international expert group.…”

Section: Introductionmentioning

confidence: 99%

Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice

Mayorandan

Meyer

Gökçay

et al. 2014

Orphanet J Rare Dis

115

163

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BackgroundHepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data.MethodsVia questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications.ResultsEarly treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 μM) and NTBC-levels in the therapeutic range (20–40 μM). Side effects of NTBC are mild and often transient.Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood).ConclusionBased on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.

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“…However, the principal challenge to recruitment relates to the intervention itself and to deeply ingrained attitudes by many in the professional and lay mitochondrial disease communities regarding placebo-controlled trials (Stacpoole, 2011a; Vockley et al, 2010). Virtually all subjects we have screened for this study have already been receiving a commercial CoQ 10 preparation as part of a nutritional cocktail prescribed by their primary caregiver and/or through their family’s efforts.…”

Section: 2 Methods and Resultsmentioning

confidence: 99%

“…Treatment of mitochondrial diseases has been generally disappointing and has usually been approached in an uncontrolled manner (Kerr, 2010; Vockley J and Vockley CM, 2010). Despite the routine use of specialized diets, nutritional supplements or investigational drugs, there is no objectively proven human therapy for any genetic mitochondrial disease that directly impacts cellular energy metabolism.…”

Section: 1 Introductionmentioning

confidence: 99%

Design and implementation of the first randomized controlled trial of coenzyme Q10 in children with primary mitochondrial diseases

et al. 2012

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We report the design and implementation of the first phase 3 trial of CoenzymeQ10 (CoQ10) in children with genetic mitochondrial diseases. A novel, rigorous set of eligibility criteria was established. The trial, which remains open to recruitment, continues to address multiple challenges to the recruitment of patients, including widely condoned empiric use of CoQ10 by individuals with proven or suspected mitochondrial disease and skepticism among professional and lay mitochondrial disease communities about participating in placebo-controlled trials. These attitudes represent significant barriers to the ethical and scientific evaluation–and ultimate approval–of nutritional and pharmacological therapies for patients with life-threatening inborn errors of energy metabolism.

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Clinical trials: Curing a critical deficiency in metabolic medicine

Cited by 12 publications

References 1 publication

Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes

Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes

Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice

Design and implementation of the first randomized controlled trial of coenzyme Q10 in children with primary mitochondrial diseases

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