X-linked Adrenoleukodystrophy Clinical Trial
— XAMNPIOP2011Official title:
Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy: a Phase II, Single-arm, Multicentric Clinical Trial
Verified date | March 2019 |
Source | Onofre, Aurora Pujol, M.D. |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 18 |
Est. completion date | July 2019 |
Est. primary completion date | March 2019 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 65 Years |
Eligibility |
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, ?GT, 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 |
Country | Name | City | State |
---|---|---|---|
Spain | Donostia University Hospital | Donostia | |
Spain | Bellvitge University Hospital | L'Hospitalet de Llobregat | Barcelona |
Lead Sponsor | Collaborator |
---|---|
Onofre, Aurora Pujol, M.D. | ELA España Association, Fundacion Hesperia, Instituto de Salud Carlos III |
Spain,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 2 Minute Walk Test (2MWT) | The score at this test corresponds to the distance traveled by the patient during 2 minutes, on a flat surface | 24 months | |
Secondary | Timed Up and Go (TUG) test | It consists in standing up, walking 3 meters, turning around, walk back to the chair and sitting back down, at regular pace | 24 months | |
Secondary | Time to walk 25 Feet (TW25) | In this test the patient should walk 7.62 meters (25 feet) as quickly, but safely, as possible without running | 24 months | |
Secondary | 6 Minute Walk Test (6MWT) | It measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface | 24 months | |
Secondary | Sensory disturbances: tactile | For the evaluation the Total Neuropathy Score (TNS) will be used (0-4) | 24 months | |
Secondary | Sensory disturbances: painful | For the evaluation the Total Neuropathy Score (TNS) will be used (0-4) | 24 months | |
Secondary | Sensory disturbances: vibratory | For the evaluation the Total Neuropathy Score (TNS) will be used (0-4) | 24 months | |
Secondary | Expanded disability status scale (EDSS) | This scale measures motor function, ranging from 0 (normal neurological examination) to 10 (death) | 24 months | |
Secondary | Dynamometer test (optional) | It measures the muscle strength | 24 months | |
Secondary | Ashworth scale | The Modified Ashworth Scale measures spasticity in patients who have lesions of the CNS or neurological disorders. The modified Ashworth scale ranges from 0 (no increase in tone) to 4 (Affected part(s) rigid in flexion or extension) | 24 months | |
Secondary | SF-Qualiveen | It measures the impact of urinary disorders in patients with neurological conditions | 24 months | |
Secondary | Revised Faecal Incontinence Scale (RFIS) | The RFIS is a short, reliable and valid five item scale used to asses faecal incontinence and to monitor patient outcomes following treatment. Response options are framed as 5-point Likert-type scales, with 0 indicating no impact of faecal incontinence problems on health-related quality of life and 4 indicating a high adverse impact. The RFIS total score is calculated by adding a person's score for each question. Adding the score for each of the five questions results in a possible score range of 0-20 | 24 months | |
Secondary | Conventional MRI | FLAIR and T2 sequences may show subtle anomalies evaluated using the Loes scoring system. This MRI severity scale has been designed specifically for X-linked adrenoleukodystrophy and has been shown to correlate with severity of neurologic deficits and to be predictive of disease progression. Different brain regions are considered in the MRI severity score. Each area is scored as 0 if normal, 0.5 if unilateral involvement, and 1 if the lesion or atrophy is bilateral. The maximum severity score is 34; a score of 1 is considered abnormal. | 24 months | |
Secondary | Diffusion tensor Imaging (DTI) | Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) will be measured | 24 months | |
Secondary | Brain MRI spectroscopy (MRS) | NAA/creatine and choline/creatine ratios will be measured | 24 months | |
Secondary | Nerve conduction studies: conduction velocity in the peroneal nerve | m/s | 24 months | |
Secondary | Nerve conduction studies: amplitude of the signal in the peroneal motor nerve | (mV) | 24 months | |
Secondary | Nerve conduction studies: conduction velocity in the sura sensitive nerve | (m/s) | 24 months | |
Secondary | Nerve conduction studies: amplitude of the signal in the sura sensitive nerve | (µV) | 24 months | |
Secondary | Motor Evoked Potentials (MEP): F wave | (ms) in right and left upper limb and right and left lower limb | 24 months | |
Secondary | Motor Evoked Potentials (MEP): Central latency | (ms) in right and left upper limb and right and left lower limb | 24 months | |
Secondary | Motor Evoked Potentials (MEP): Amplitude | (µV) in right and left upper limb and right and left lower limb | 24 months | |
Secondary | Motor Evoked Potentials (MEP): Central motor conduction time | (ms) in right and left upper limb and right and left lower limb | 24 months | |
Secondary | Somatosensory Evoked Potentials (SSEP): Latency N9 | (ms) right and left arms | 24 months | |
Secondary | Somatosensory Evoked Potentials (SSEP): Latency N13 | (ms) right and left arms | 24 months | |
Secondary | Somatosensory Evoked Potentials (SSEP): Latency N20 | (ms) right and left arms | 24 months | |
Secondary | Somatosensory Evoked Potentials (SSEP): Amplitude N20 | (µV) right and left arms | 24 months | |
Secondary | Somatosensory Evoked Potentials (SSEP): Latency N8 | (ms) right and left legs | 24 months | |
Secondary | Somatosensory Evoked Potentials (SSEP): Latency N22 | (ms) right and left legs | 24 months | |
Secondary | Somatosensory Evoked Potentials (SSEP): Latency P40 | (ms) right and left legs | 24 months | |
Secondary | Somatosensory Evoked Potentials (SSEP): Amplitude N40 | (µV) right and left legs | 24 months | |
Secondary | Brainstem Auditory Evoked Potentials (BAEP): Latency I wave | (ms) right and left | 24 months | |
Secondary | Brainstem Auditory Evoked Potentials (BAEP): Latency III wave | (ms) right and left | 24 months | |
Secondary | Brainstem Auditory Evoked Potentials (BAEP): Latency V wave | (ms) right and left | 24 months | |
Secondary | Brainstem Auditory Evoked Potentials (BAEP): Latency I-III wave | (ms) right and left | 24 months | |
Secondary | Brainstem Auditory Evoked Potentials (BAEP): Latency III-V wave | (ms) right and left | 24 months | |
Secondary | Brainstem Auditory Evoked Potentials (BAEP): Latency I-V wave | (ms) right and left | 24 months | |
Secondary | Markers of oxidative stress: GSA | Glutamic semialdehyde (GSA) will be measured in plasma. Results will be expressed in µmol/mol lysine | 24 months | |
Secondary | Markers of oxidative stress: CEL | Carboxyethyl-lysine (CEL) will be measured in plasma. Results will be expressed in µmol/mol lysine | 24 months | |
Secondary | Markers of oxidative stress: MDAL | N2-malondialdehyde-lysine (MDAL) will be measured in plasma. Results will be expressed in µmol/mol lysine | 24 months | |
Secondary | Markers of oxidative stress: CML | N2-carboxymethyl-lysine (CML) will be measured in plasma. Results will be expressed in µmol/mol lysine | 24 months | |
Secondary | Markers of oxidative stress: 8-oxoDG | 7,8-dihydro-8-oxo-2-deoxyguanosine (8-oxoDG) will be measured in urine. Results will be expressed in ng/mg creatine | 24 months | |
Secondary | Markers of inflammation: HGF | HGF will be measured in plasma. Results will be expressed in pg/ml | 24 months | |
Secondary | Markers of inflammation: IL6 | IL6 will be measured in plasma. Results will be expressed in pg/ml | 24 months | |
Secondary | Markers of inflammation: IL8 | IL8 will be measured in plasma. Results will be expressed in pg/ml | 24 months | |
Secondary | Markers of inflammation: MCP-1 | MCP-1 will be measured in plasma. Results will be expressed in pg/ml | 24 months | |
Secondary | Markers of inflammation: NGF | NGF will be measured in plasma. Results will be expressed in pg/ml | 24 months | |
Secondary | Markers of inflammation: TNF | TNF will be measured in plasma. Results will be expressed in pg/ml | 24 months | |
Secondary | Markers of inflammation: adiponectin | Adiponectin will be measured in plasma. Results will be expressed in µg/ml | 24 months | |
Secondary | Markers of inflammation: CCR3 | CCR3 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression | 24 months | |
Secondary | Markers of inflammation: CXCL5 | CXCL5 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression | 24 months | |
Secondary | Markers of inflammation: CXCL9 | CXCL9 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression | 24 months | |
Secondary | Markers of inflammation: IL9R | IL9R will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression | 24 months | |
Secondary | Markers of inflammation: PPARd | PPARd will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression | 24 months | |
Secondary | Markers of inflammation: GPX4 | GPX4 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression | 24 months | |
Secondary | Markers of inflammation: STAT1 | STAT1 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression | 24 months |
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