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Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy (XAMNPIOP2011)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03864523
Recruitment Status : Completed
First Posted : March 6, 2019
Last Update Posted : September 10, 2019
Sponsor:
Collaborators:
Instituto de Salud Carlos III
Fundacion Hesperia
ELA España Association
Information provided by (Responsible Party):
Onofre, Aurora Pujol, M.D.

Brief 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.


Condition or disease Intervention/treatment Phase
Adrenomyeloneuropathy X-linked Adrenoleukodystrophy Drug: Pioglitazone Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy: a Phase II, Single-arm, Multicentric Clinical Trial
Study Start Date : January 2016
Actual Primary Completion Date : March 2019
Actual Study Completion Date : July 2019


Arm Intervention/treatment
Experimental: XAMNPIO
Pioglitazone 15 mg tablets 2/day during 2 years
Drug: Pioglitazone



Primary Outcome Measures :
  1. 2 Minute Walk Test (2MWT) [ Time Frame: 24 months ]
    The score at this test corresponds to the distance traveled by the patient during 2 minutes, on a flat surface


Secondary Outcome Measures :
  1. Timed Up and Go (TUG) test [ Time Frame: 24 months ]
    It consists in standing up, walking 3 meters, turning around, walk back to the chair and sitting back down, at regular pace

  2. Time to walk 25 Feet (TW25) [ Time Frame: 24 months ]
    In this test the patient should walk 7.62 meters (25 feet) as quickly, but safely, as possible without running

  3. 6 Minute Walk Test (6MWT) [ Time Frame: 24 months ]
    It measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface

  4. Sensory disturbances: tactile [ Time Frame: 24 months ]
    For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)

  5. Sensory disturbances: painful [ Time Frame: 24 months ]
    For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)

  6. Sensory disturbances: vibratory [ Time Frame: 24 months ]
    For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)

  7. Expanded disability status scale (EDSS) [ Time Frame: 24 months ]
    This scale measures motor function, ranging from 0 (normal neurological examination) to 10 (death)

  8. Dynamometer test (optional) [ Time Frame: 24 months ]
    It measures the muscle strength

  9. Ashworth scale [ Time Frame: 24 months ]
    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)

  10. SF-Qualiveen [ Time Frame: 24 months ]
    It measures the impact of urinary disorders in patients with neurological conditions

  11. Revised Faecal Incontinence Scale (RFIS) [ Time Frame: 24 months ]
    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

  12. Conventional MRI [ Time Frame: 24 months ]
    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.

  13. Diffusion tensor Imaging (DTI) [ Time Frame: 24 months ]
    Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) will be measured

  14. Brain MRI spectroscopy (MRS) [ Time Frame: 24 months ]
    NAA/creatine and choline/creatine ratios will be measured

  15. Nerve conduction studies: conduction velocity in the peroneal nerve [ Time Frame: 24 months ]
    m/s

  16. Nerve conduction studies: amplitude of the signal in the peroneal motor nerve [ Time Frame: 24 months ]
    (mV)

  17. Nerve conduction studies: conduction velocity in the sura sensitive nerve [ Time Frame: 24 months ]
    (m/s)

  18. Nerve conduction studies: amplitude of the signal in the sura sensitive nerve [ Time Frame: 24 months ]
    (μV)

  19. Motor Evoked Potentials (MEP): F wave [ Time Frame: 24 months ]
    (ms) in right and left upper limb and right and left lower limb

  20. Motor Evoked Potentials (MEP): Central latency [ Time Frame: 24 months ]
    (ms) in right and left upper limb and right and left lower limb

  21. Motor Evoked Potentials (MEP): Amplitude [ Time Frame: 24 months ]
    (μV) in right and left upper limb and right and left lower limb

  22. Motor Evoked Potentials (MEP): Central motor conduction time [ Time Frame: 24 months ]
    (ms) in right and left upper limb and right and left lower limb

  23. Somatosensory Evoked Potentials (SSEP): Latency N9 [ Time Frame: 24 months ]
    (ms) right and left arms

  24. Somatosensory Evoked Potentials (SSEP): Latency N13 [ Time Frame: 24 months ]
    (ms) right and left arms

  25. Somatosensory Evoked Potentials (SSEP): Latency N20 [ Time Frame: 24 months ]
    (ms) right and left arms

  26. Somatosensory Evoked Potentials (SSEP): Amplitude N20 [ Time Frame: 24 months ]
    (μV) right and left arms

  27. Somatosensory Evoked Potentials (SSEP): Latency N8 [ Time Frame: 24 months ]
    (ms) right and left legs

  28. Somatosensory Evoked Potentials (SSEP): Latency N22 [ Time Frame: 24 months ]
    (ms) right and left legs

  29. Somatosensory Evoked Potentials (SSEP): Latency P40 [ Time Frame: 24 months ]
    (ms) right and left legs

  30. Somatosensory Evoked Potentials (SSEP): Amplitude N40 [ Time Frame: 24 months ]
    (μV) right and left legs

  31. Brainstem Auditory Evoked Potentials (BAEP): Latency I wave [ Time Frame: 24 months ]
    (ms) right and left

  32. Brainstem Auditory Evoked Potentials (BAEP): Latency III wave [ Time Frame: 24 months ]
    (ms) right and left

  33. Brainstem Auditory Evoked Potentials (BAEP): Latency V wave [ Time Frame: 24 months ]
    (ms) right and left

  34. Brainstem Auditory Evoked Potentials (BAEP): Latency I-III wave [ Time Frame: 24 months ]
    (ms) right and left

  35. Brainstem Auditory Evoked Potentials (BAEP): Latency III-V wave [ Time Frame: 24 months ]
    (ms) right and left

  36. Brainstem Auditory Evoked Potentials (BAEP): Latency I-V wave [ Time Frame: 24 months ]
    (ms) right and left

  37. Markers of oxidative stress: GSA [ Time Frame: 24 months ]
    Glutamic semialdehyde (GSA) will be measured in plasma. Results will be expressed in μmol/mol lysine

  38. Markers of oxidative stress: CEL [ Time Frame: 24 months ]
    Carboxyethyl-lysine (CEL) will be measured in plasma. Results will be expressed in μmol/mol lysine

  39. Markers of oxidative stress: MDAL [ Time Frame: 24 months ]
    N2-malondialdehyde-lysine (MDAL) will be measured in plasma. Results will be expressed in μmol/mol lysine

  40. Markers of oxidative stress: CML [ Time Frame: 24 months ]
    N2-carboxymethyl-lysine (CML) will be measured in plasma. Results will be expressed in μmol/mol lysine

  41. Markers of oxidative stress: 8-oxoDG [ Time Frame: 24 months ]
    7,8-dihydro-8-oxo-2-deoxyguanosine (8-oxoDG) will be measured in urine. Results will be expressed in ng/mg creatine

  42. Markers of inflammation: HGF [ Time Frame: 24 months ]
    HGF will be measured in plasma. Results will be expressed in pg/ml

  43. Markers of inflammation: IL6 [ Time Frame: 24 months ]
    IL6 will be measured in plasma. Results will be expressed in pg/ml

  44. Markers of inflammation: IL8 [ Time Frame: 24 months ]
    IL8 will be measured in plasma. Results will be expressed in pg/ml

  45. Markers of inflammation: MCP-1 [ Time Frame: 24 months ]
    MCP-1 will be measured in plasma. Results will be expressed in pg/ml

  46. Markers of inflammation: NGF [ Time Frame: 24 months ]
    NGF will be measured in plasma. Results will be expressed in pg/ml

  47. Markers of inflammation: TNF [ Time Frame: 24 months ]
    TNF will be measured in plasma. Results will be expressed in pg/ml

  48. Markers of inflammation: adiponectin [ Time Frame: 24 months ]
    Adiponectin will be measured in plasma. Results will be expressed in μg/ml

  49. Markers of inflammation: CCR3 [ Time Frame: 24 months ]
    CCR3 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression

  50. Markers of inflammation: CXCL5 [ Time Frame: 24 months ]
    CXCL5 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression

  51. Markers of inflammation: CXCL9 [ Time Frame: 24 months ]
    CXCL9 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression

  52. Markers of inflammation: IL9R [ Time Frame: 24 months ]
    IL9R will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression

  53. Markers of inflammation: PPARd [ Time Frame: 24 months ]
    PPARd will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression

  54. Markers of inflammation: GPX4 [ Time Frame: 24 months ]
    GPX4 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression

  55. Markers of inflammation: STAT1 [ Time Frame: 24 months ]
    STAT1 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03864523


Locations
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Spain
Bellvitge University Hospital
L'Hospitalet de Llobregat, Barcelona, Spain, 08908
Donostia University Hospital
Donostia, Spain, 20080
Sponsors and Collaborators
Onofre, Aurora Pujol, M.D.
Instituto de Salud Carlos III
Fundacion Hesperia
ELA España Association

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Responsible Party: Onofre, Aurora Pujol, M.D.
ClinicalTrials.gov Identifier: NCT03864523     History of Changes
Other Study ID Numbers: XAMNPIOAP2011
First Posted: March 6, 2019    Key Record Dates
Last Update Posted: September 10, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Onofre, Aurora Pujol, M.D.:
AMN
pioglitazone
Additional relevant MeSH terms:
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Adrenoleukodystrophy
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Hereditary Central Nervous System Demyelinating Diseases
Leukoencephalopathies
Demyelinating Diseases
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Metabolism, Inborn Errors
Peroxisomal Disorders
Metabolic Diseases
Adrenal Insufficiency
Adrenal Gland Diseases
Endocrine System Diseases
Pioglitazone
Hypoglycemic Agents
Physiological Effects of Drugs