General Information

ONGOING studies and trials for a-t

IB1001 TRIAL

Location: United States (CA), United Kingdom

Investigator: IntraBio, Inc.

Purpose: This open label, rater blinded study is being performed to determine the efficacy of N-Acetyl-L-Leucine (IB1001) to treat certain neurological symptoms associated with A-T. Detailed information about this trial can be found at clinicaltrials.gov. (ClinicalTrials.gov Identifier: NCT03759678).

Machine Vision and Learning for A-T Neurophenotypes

Location: Virtual (US only)

Investigator: Anoopum Gupta, MD, PhD

Purpose: The purpose of this study is to develop sensitive, automated and objective means of measuring neurological disease severity for 1) use in clinical trials of potential therapies and 2) aiding the earlier diagnosis of A-T, especially milder forms of the disease.

To develop these objective quantitative measures, Dr. Gupta will train a computer system to analyze video, audio and potentially other types of digital data captured from individuals with A-T. The system will then identify patterns in the data that are specific to A-T, using an artificial intelligence technique known as “machine learning.”

For more information, please contact Jennifer Thornton, A-TCP Executive Director at 954.481.6611 or jennifer@atcp.org.

global a-t family data platform

Location: Virtual at atfamilies.org

Investigator: A-T Children’s Project

Purpose: The Global A-T Family Data Platform is a patient-driven effort through which health information, genetic and other types of data about people with A-T are shared with researchers. This platform enables researchers to access important patient data from around the world quickly, securely and efficiently, hopefully leading to new discoveries. For more information and to participate, please visit atfamilies.org.

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ONGOING natural history studies at the A-T clinical center at johns hopkins hospital

Pulmonary Function Study

Investigator: Sharon McGrath-Morrow, MD

Purpose: The major goal of this project is to determine the feasibility of performing standardized pulmonary function testing in children with ataxia-telangiectasia and to collect cross-sectional and longitudinal data on lung function in individuals with A-T to establish the natural history of pulmonary function decline in this population.

Eligibility Requirements: 6 years and older and able to follow directions and perform breathing maneuvers in a controlled fashion.

Participants recruited only during regularly scheduled A-T Clinical Center visits or meetings for patients with A-T.

Benefits: No immediate benefit to participants but may help medical treatment in the future.

Swallowing Study

Investigator: Maureen Lefton-Greif, PhD

Purpose: Two goals of this study are to develop non-invasive markers that will (1) lessen the impact of swallowing dysfunction by facilitating early identification of oropharyngeal dysphagia for the prompt initiation of appropriate treatment and (2) serve as biomarkers for disease progression or clinical trials.

Eligibility Requirements: 6 years or older and able to participate in procedures for recordings of respiration during swallowing and phonation; previously evaluated at the A-T Clinical Center at Hopkins or must provide medical records that confirm the diagnosis of A-T.

Participants recruited only during regularly scheduled A-T Clinical Center visits or meetings for patients with A-T

Benefits: No immediate benefit to participants but may help medical treatment in the future.

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Completed clinical studies and trials for a-t

ATTeST

Location: Global, multi-site

Investigator: EryDel, S.p.A.

Purpose: This large placebo controlled, cross-over trial assessed the safety and efficacy of the EryDex System (dexamethasone sodium phosphate loaded red blood cells) to treat neurological symptoms associated with A-T. For more information, please visit the ATTeST website.

Conclusions: Data analysis ongoing.

NICOTINAMIDE RIBOSIDE (NIAGEN®) PROOF-OF-CONCEPT STUDY

Location: The Netherlands

Investigator: Michel Willemsen, MD, PhD

Purpose: This 4-month open labeled, explorative trial was performed to examine certain laboratory markers and neurological symptoms, quality of life, and potential adverse effects in participants with A-T treated with nicotinamide ribose (Niagen®, ChromaDex).

Conclusions: Data analysis ongoing.

PET Scan/fMRI Study

Location: Brookhaven National Laboratory (BNL), USA

Investigator: Nora Volkow, MD

Purpose: To assess brain activity in adult patients with A-T. An understanding of brain metabolism or activity in A-T may lead to the identification of potential therapeutic targets for this disease.

Conclusions: Participants with A-T demonstrated lower brain activity or metabolism in the cerebellum as compared to control participants. This result is not unexpected, as this area of the brain is particularly vulnerable in A-T and undergoes cell loss as the disease progresses. Adult participants with A-T also demonstrated increased metabolism in an area of the brain known as the globus pallidus, which helps regulate movements. This increased activity in the globus pallidus was correlated with decreased motor performance in the participants with A-T. Further studies are needed to corroborate these new findings; however, the “over active” globus pallidus may represent a target for therapeutic intervention for A-T.

Reference: Volkow, N.D., Tomasi, D., Wang, G.J., Studentsova, Y., Margus, B., and Crawford, T.O. (2014). Brain glucose metabolism in adults with ataxia-telangiectasia and their asymptomatic relatives. Brain 137, 1753-17

Baclofen Study

Location: A-T Clinical Center at Johns Hopkins Hospital

Investigator:Thomas O. Crawford, MD

Purpose: This placebo controlled cross-over trial was performed to determine if treatment with the drug Baclofen improves balance and tremor as well as certain eye movement abnormalities associated with A-T.

Conclusions: At the dose used – 10 mg tablets with dose escalation up to a maximum dose of 30 mg / day – Baclofen did not have a significant effect on tremor, eye movement or balance deficits in the study participants. Higher doses of baclofen, or alternative drugs, may be useful and are worth trying. The tests used to measure eye movements, balance and tremor were proven accurate and suitable for use in future trials.

Dexamethasone Trial

Location: Italy

Investigator: Luciana Chessa, MD

Purpose: This open label (non-placebo controlled) study was performed to assess the safety and tolerability of the EryDex System in patients with A-T, and examine the ability of the EryDex System to reduce the neurological symptoms associated with A-T.

EryDex System: EryDex is dexamethasone sodium phosphate loaded patient erythrocytes (red blood cells or RBCs).  RBCs are removed from the patient, mechanically loaded with dexamethasone, then re-infused back into the patient. The EryDex System allows the slow release of dexamethasone, thus maintaining a sustained, low dose of drug in the blood stream for a one month period after loading.

Conclusions: The EryDex system significantly reduced the neurological symptoms associated with A-T as measured by the International Cooperative Ataxia Rating Scale (ICARS). No steroid side effects were observed.

Reference: Chessa, L., Leuzzi, V., Plebani, A., Soresina, A., Micheli, R., D’Agnano, D., Venturi, T., Molinaro, A., Fazzi, E., Marini, M., et al. (2014). Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia patients: results of a phase 2 trial. Orphanet J Rare Dis 9, 5.

Betamethasone Trials

Location: Italy

Investigator: Luciana Chessa, MD

Purpose: To perform a placebo controlled trial of low dose bethamethasone for the reduction of neurological symptoms associated with A-T.

Conclusions: Oral betamethosone (0.1 mg/kg/day) effectively reduced the ataxic symptoms of patients with A-T as measured by the International Cooperative Ataxia Rating Scale (ICARS).

Reference: Zannolli, R., Sabrina, B., Betti, G., Salvucci, S., Plebani, A., Soresina, A., Pietrogrande, M.C., Martino, S., Leuzzi, V., Finocchi, A., et al. (2012). A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia. Mov Disord 27, 1312-1316.

Location: Italy

Investigator: Claudio Pignata, MD

Purpose: This small open label (non-placebo controlled) trial was performed to evaluate the minimum therapeutically effective dosage of bethamethasone, a corticosteroid, on the neurological symptoms of A-T.

Conclusions: Bethamethasone at very low dosage (0.03 mg/kg/day) is effective at improving neurological signs in patients affected with ataxia-telangiectasia. However, as previously shown, a worsening of the neurological signs was noted after the washout periods. In the near future, it will be important to define whether a prolongation of the treatment will lead to the persistence of the neurological improvement. A long-term study with low dosage would also help define the benefit to risk ratio of such therapeutic intervention to address the concern of the immunosuppressive effect on infection susceptibility in these patients..

Reference: Broccoletti, T., Del Giudice, E., Cirillo, E., Vigliano, I., Giardino, Gl, Ginocchio, V.M., Bruscoli, S., Riccardi, C., and Pignata, C. (2011). Efficacy of very-low-dose betamethasone on neurological symptoms of ataxia-telangiectasia. Eur Neurol 18, 564-570.

Effect of Amantadine on Movement Disorder in A-T

Location: Sheba Medical Center, Israel

Investigator: Andreea Nissenkorn, MD

Purpose: This open label (non-placebo controlled) trial was performed to determine if amantadine sulphate improves ataxia and some of the other movement disorders (example: bradykinesia, dystonia, chorea) in patients with A-T.

Conclusions: Participants were treated with amantadine for 8 weeks (mean dosage at the end of the study was 6.3+0.87 mg/kg/day). Ataxia was assessed using the International Cooperative Ataxia Scale (ICARS), parkinsonism was assessed by the Unified Parkinson Disease Rating Scale (UPDRS), and involuntary movements by the Abnormal Involuntary Movement Scale (AIMS). The majority of patients in this trial (~76%) demonstrated significant improvements with regards to parkinsonism, ataxia and involuntary movements. Observed side effects of amantadine were mild and transient and did not lead to discontinuation of treatment. Amantadine is a well tolerated and effective treatment for the motor symptoms associated with A-T.  A double blind, placebo-controlled trial is warranted to assess long term treatment with this drug.

Reference: Nissenkorn, A., Hassin-Baer, S., Lerman, S.F., Levi, Y.B., Tzadok, M., and Ben-Zeev, B. (2013). Movement disorder in ataxia-telangiectasia: treatment with amantadine sulfate. J Child Neurol 28, 155-160.

Cerebrospinal Fluid Biomarker Study

Location: Indiana University School of Medicine (proteomics analysis); A-T Clinical Center, Johns Hopkins Hospital (cerebrospinal fluid collection)

Investigators: Mu Wang, PhD (Indiana); Howard M. Lederman, MD PhD (Johns Hopkins)

Purpose: To identify markers within patient cerebrospinal fluid (CSF) which represent signs of disease or disease progression and which can be monitored to determine drug effectiveness in a clinical trial.

Conclusions: Among the 204 identified CSF proteins in this study, 13 showed significant changes in A-T patients versus control samples. These 13 proteins are either involved in neurodegenerative disorders or cancer. Further study of these proteins could provide insights into their use as potential therapeutic targets for the treatment of A-T and their potential as biomarkers that can be used to monitor or predict A-T disease progression.CSF may not be ideal due to the invasiveness involved in sample collection. Therefore, future studies involving blood samples would make this biomarker discovery strategy even more attractive, with the hope that such noninvasive biospecimens can be incorporated into routine clinical practice and utilized in clinical trials for the assessment of potential therapeutic compounds.

Reference: Dzieciatkowska, M., Qi, G., You, J., Bemis, K.G., Sahm, H., Lederman, H.M., Crawford, T.O., Gelbert, L.M., Rothblum-Oviatt, C., and Wang, M. (2011). Proteomic Characterization of Cerebrospinal Fluid from Ataxia-Telangiectasia (A-T) Patients Using a LC/MS-Based Label-Free Protein Quantification Technology. Int J Proteomics 2011, 578903.

OxiDative Stress Clinical Trial

Location: A-T Clinical Center, Johns Hopkins Hospital

Investigator: Howard M. Lederman, MD PhD

Purpose: This placebo controlled, cross-over trial was performed to determine the safety of, and identify laboratory markers for treatment with a combination of nicotinamide and the antioxidant alpha-lipoic acid, compounds that may slow the brain cell death associated with A-T.

Conclusions: 200 mg of alpha-lipoic acid was administered three times per day and 12.5 mg/kg of nicotinamide was administered two times per day. For the first two months, participants were randomly selected to receive either a) alpha-lipoic acid + placebo for nicotinamide or b) nicotinamide + placebo for alpha lipoic acid, then each group “crossed over” or switched compounds for the next two months. For the final two months of the trial, all participants were treated with both compounds.

Two laboratory markers of oxidative stress significantly improved when participants took both alpha-lipoic acid and nicotinamide. A trend toward increased lymphocyte counts was also observed, but did not reach statistical significance. None of these changes was thought to be clinically important. However, these findings will form the basis for examination of other laboratory markers of oxidative stress in future trials of novel antioxidant treatments. In addition, this study allowed for the development of accurate and reproducible methods for measuring the lung function of patients with A-T which can also be used in future clinical studies or trials.

 L-Dopa Treatment Trial

Location: A-T Clinical Center, Johns Hopkins Hospital

Investigators: Howard M. Lederman, MD PhD, Thomas O. Crawford, MD

Purpose: This small, double blind, placebo controlled trial was performed to determine if L-Dopa had therapeutic benefit for any of the neurologic symptoms associated with A-T.

Conclusions: L-Dopa (Sinemet [Levodopa 100 mg / carbidopa 10 mg]) treatment was gradually increased from one pill per day for four days, to two pills per day for four days, to three pills per day for four days in an attempt to provide maximum improvement with the least side-effects. The maxium dose was maintained for the duration of the trial.

Although individual patients perceived some benefit in one or more areas, no overall consistent improvement in neurologic function was observed. Further, targeted studies may be warranted.

Inositol Treatment Trial

Location: The Children’s Hospital of Philadelphia (CHOP)

Investigators: Gerard Berry, MD

Purpose: To determine if inositol has therapeutic benefit for total lymphocyte count or ataxia.

Conclusions: No beneficial effect of inositol on total lymphocyte count or ataxia was seen. Some parents/caregivers reported an improvement in mood or behavior in their children.

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