Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy

• Status: Completed
• Trial end date: 2019-07-01
• Target enrollment: 0
• Participant gender: All

Summary

X-linked adrenoleukodystrophy is a rare, demyelinating and neurodegenerative disorder, due to loss of function of a fatty acid transporter, the peroxisomal ABCD1 protein. Its more frequent phenotype, the adrenomyeloneuropathy in adults, is characterized by axonal degeneration in spinal cord, spastic paraparesis and a disabling peripheral neuropathy. Actually, there is no efficient treatment for the disease. The work of the researchers in the last twelve years dissecting the physiopathological basis of the disorder has uncovered an involvement of the early oxidative stress in the neurodegenerative cascade and mitocondrial depletion. In a preclinical trial they have observed that pioglitazone, a PPARγ/PGC-1α axis metabolic activator with immunomodulatory, anti-inflammatory and antioxidant response regulator properties, efficiently reverse the clinical symptoms and the axonal degeneration in the mouse model for the disease and normalize stress and mitochondrial depletion biomarkers.

The researchers will test the effectiveness of the drug in terms of motor function and correction of oxidative damage markers in proteins and DNA and inflammation markers in an open trial. Fifteen-twenty patients will be included and clinically explored and assessed in the HU of Bellvitge and the HU of Donostia using clinical scales for spasticity, evoked potentials, electroneurinograms and cranial RMN. The information will be collected in a data base that will be of great value to improve the present attention and the future follow-up of the patients and to facilitate their inclusion in therapeutic randomized, double blind, against placebo, multicentric and international clinical trials.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Onofre, Aurora Pujol, M.D.
• Collaborators: ELA España Association; Fundacion Hesperia; Instituto de Salud Carlos III
• Treatments: Pioglitazone

Criteria

Inclusion Criteria:

• Clinical signs of AMN with at least pyramidal signs in the lower limbs and difficulties to run.

• Presence of motor deficit according to the EDSS scale

• Ability to perform the 2MWT

• Normal brain MRI or brain MRI showing abnormalities that can be observed in AMN patients without cerebral form of X-ALD with a maximum Loes score of 4

• Ejection fraction > 50% at echocardiogram

• Normal electrocardiogram

• Normal urine cytology

• Normal liver function, as assessed by plasma ASAT, ALAT, PAL, γGT, bilirubin measures (≤2.5-fold normal values)

• Normal kidney function as assessed by plasma urea, creatinin (≤ 2-fold normal values)

• Appropriate steroid replacement if adrenal insufficiency is present

• Informed consent

• Affiliated to the Spanish Public Health System

Exclusion Criteria:

• Gadolinium enhancement on T1 sequence of any abnormal hypersignal of white matter, including myelinated pyramidal tracts, visible at brain MRI on FLAIR sequences

• Brain MRI abnormalities of the "AMN type" with a Loes score > 4

• Any abnormal hypersignal of white matter visible on FLAIR sequences other than of "AMN type" and related to X-ALD

• Patients taking pioglitazone or another glitazone during the past 6 months

• Diabetic patients (type I or II)

• Fasting blood glucose > 125 mg/L

• Glycosylated hemoglobin > 6%

• History of heart failure

• Heart failure (NYHA III to IV) or ejection fraction ≤ 50%

• History of cardiac disease

• [Hemoglobin] < 13g/dl in males, <12 g/dl in women

• Absolute neutrophil count (ANC) <1500 cells/mm3

• Platelet count <100,000 cells/mm3

• Significant peripheral edema (2+ or more on the Assessment Chart for Pitting Edema) of the extremities of any etiology

• Any evolutive malignancy during the last five years

• Prior or current bladder cancer

• Smokers (one pack/ day or more for at least 20 years), current or former

• Women with history of osteoporosis

• Menopaused woman with T-score < -2.5 on osteodensitometry measurement

• Any evolutive medical disease other than AMN

• Any psychiatric disease

• Pregnant or breastfeeding woman

• Either no pre-menopaused woman or no menopaused woman not taking any contraceptive method

• Hereditary intolerance to galatose, or malabsorption of glucose or galactose due the presence of monohydrated lactose.

• Hypersensibility to the active substance or to galactose (excipient)

• Concomitant treatment with cytochrome P450 CYP 2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin)

• Taking of either vitamin A, E or lipoic acid during the past 3 months

• Contraindications for MRI procedure such as subjects with paramagnetic materials in the body, such as aneurysm clips, pacemakers, intraocular metal or cochlear implants

• Present participation to another therapeutic clinical trial for ALD

• Not easily contactable by the investigator in case of emergency or not capable to call the investigator

• Gross hematuria of unknown origin