Evaluation of the Effects of Calcitriol's in the Neurological Symptoms of Friedreich's Ataxia Patients

Pilot Trial About the Effects of Calcitriol's Treatment in the Neurological Function and Frataxin's Level in Friedreich's Ataxia Patients

Friedreich's Ataxia (FA) is an autosomal recessive disease the mutation of which leads to a deficiency of a protein called frataxin, which is responsible for the symptoms of the disease. It is assumed that inducing an increase in the production of frataxin could reverse part of the disease's symptoms.

Several treatments with drugs that raise frataxin levels have been tested, but they have either have not given the expected result or have induced intolerable side effects. The IRBLleida (Institut de Recerca Biomèdica de Lleida Fundació Dr. Pifarré) team has shown that calcitriol can increase the production of frataxin up to 2.5 to 3 times, a higher proportion than any of the drugs previously tested. For that reason, the next step in our research would be to check the effects of this drug (Calcitriol 0.25mcg/24h for a year) in patients with FA. On the other hand, calcitriol, the active form of vitamin D, is a drug with a very low rate of adverse effects that has been used for decades. Therefore, it is a drug with a very well established tolerability. The results of the present study, if positive, would lead to the organization of trials at a larger scale, and they would allow the use of an effective treatment for patients with FA.

Friedreich's Ataxia (FA) is a recessive hereditary disease due to GAA (Guanine-Adenosine-Adenosine) triplet repeats in the FXN (Frataxin) gene. This gene codifies for the frataxin protein, the lack of which produces the neurological and cardiac symptoms.

The exact mechanisms why the lack of frataxin produces the disease aren't well understood, but it is known that frataxin is located in the mitochondria. Calcitriol synthesis, a mitochondrial process, could be impaired in FA due the reduction of CYP27B1 (Cytochrome P450, family 27, subfamily B, member 1) and Fdx1.

Because of some studies have shown that Calcitriol (the active form of D Vitamin) could raise the frataxin levels, it could have a beneficial effect in patients with FA.

Description of the trial: to assess the effect of Calcitriol 0.25mcg/24h for a year in the neurological function of FA patients.

Main objective of the trial: to evaluate the effects of Calcitriol in the neurological symptoms of patients with FA.

The second objectives of the trial are:

1. To evaluate the safety and the risk of hypercalcemia with the treatment with low dosis of Calcitriol (0.25mcg of Calcitriol every 24h) in patients with FA.
2. To measure de change in the Frataxin's levels during the treatment with Calcitriol.
3. To evaluate the effects of Calcitriol in the daily life activities and the life quality of the patients with FA.

Sample size: The number of participants needed to compleat the trial is 20. Duration: The duration of the trial is one year

Procedure:

• Before taking part in the study, it will be ensured that participants fulfill all the inclusion criteria with a detailed questionnaire.
• During the clinical trial the following test will be done: 4 electrocardiogram, 5 blood analysis to control de risk of hypercalcemia and to measure the frataxin's levels, and 3 full neurological examinations.

Post trial treatment details:

The patients who wish to continue with the treatment will be allowed to do so, at least until the results of the comparison of the basal neurological evaluation with the second and the final neurological evaluation are obtained.

If the results are positive, the treatment will be continued with regular blood tests controls.

If the results don't demonstrate a statistically significant effect, the treatment will be interrupted in all patients.

Inclusion Criteria:

• Patients with Friedreich's Ataxia and confirmed genetic diagnosis with:

  • Two pathological GAA triplet repeats in the gen FXN
  • One pathological GAA triplet repeat and one point mutation in the gen FXN

• Patients between 16 and 65 years of age.

• To keep the walking ability, although an external aid is needed.

• Women with confirmed genetic diagnosis must use an effective contraceptive method during the trial.

Exclusion Criteria:

• Any neurological or other kind of disease that could interfere in the trial according to the investigator judgement.

• Severe visual loss.

• Severe auditory loss.

• Cognitive decline*.

  • Dementia or affective-cognitive cerebellar syndrome.

• Serious psychiatric illness during the six previous months of the trial inclusion.

• Substance abuse during the six previous months of the trial inclusion.

• Severe drug allergy.

• Cardiac disease:

  • Ejection fraction <40% [N: 50-70%]
  • Heart failure > 2 from NYHA (New York Heart Association) criteria.
  • Significant valvular heart disease.
  • Symptomatic coronary artery disease.
  • Cardiac arrhythmia with hemodynamic compromise (atrial fibrillation).

• Prolonged immobilisation

• Use of research drugs during the 30 previous days of the trial inclusion.

• Concomitant treatment with digoxin, thiazide diuretics, cholestyramine, corticoids, laxatives with magnesium, barbiturates and antiepileptic drugs. Use of Calcium or Vitamin D drugs during the 30 previous days of the trial inclusion.

• Legally or mentally incapacitated person.

• In women:

  • Positive pregnancy test.
  • Maternal breastfeeding.

• Blood test alteration:

  • Hypercalcemia.
  • Elevated creatinine.