- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03864523
Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy (XAMNPIOP2011)
Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy: a Phase II, Single-arm, Multicentric Clinical Trial
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.
Study Overview
Status
Intervention / Treatment
Detailed Description
Proof of concept for this trial is provided by the results of biochemical, neuropathological and motor effects of pioglitazone in two mouse models of AMN. Pioglitazone was given orally (9 mg/kg/day) for two months in both models.
The Abcd1-null mouse model already shows at 3,5 months biochemical signs oxidative stress that increase with time and are then associated with energy homeostasis alterations, although first clinical signs of AMN-i.e. axonopathy and locomotor impairment-appear at 20 months. In these mice, there are mitochondrial anomalies, decreased levels of PGC-1α which is a master regulator of mitochondrial biogenesis, and decreased levels and activity of SIRT1α, which activates PGC-1α.
The Abcd1-null mouse can be considered as a "AMN-like" model, because of the absence of demyelinating lesions in brain and spinal cord, the presence of non-inflammatory ''dying-back'' axonopathy in peripheral nerves and spinal cord and its late-onset motor deficits that all are hallmarks of AMN in X-ALD patients. This model was used to assess the efficacy of pioglitazone on several biochemical markers in the spinal cord of Abcd1-null mice (N=12), using comparisons with placebo-¬treated Abcd1-null mice (N=12) or wild-type mice (N=12).
In Abcd1-null mice treated with pioglitazone at 10,5 months of age and studied at 12 months (1,5 months following the beginning of the ongoing treatment), mitochondrial anomalies were corrected to the level of wild type control mice. Indeed, mitochondrial DNA and protein (including PGC-1α, NRF1 and TFAM) levels were corrected; as well as mitochondrial metabolism, as assessed by pyruvate kinase activity, ATP and NAD+ concentrations. Pioglitazone had no effect on SIRT1 expression (mRNA and protein levels). However, pioglitazone significantly lowered the carbonylation of SIRT1 protein, which presumably accounts for the observed rescue of SIRT1 activity.
In these mice treated with pioglitazone, oxidative lesions in the spinal cord were reversed. Studied oxidative stress biomarkers included markers of oxidative lesions to proteins (GSA, AASA), lipids (MDAL) and carbohydrates (CEL). Additionally, the activity and concentration level of antioxidant enzymes GPX1, which were increased in untreated Abcd1-null mice, but not SOD2, was normalized to the level of wild type mice.
The second mouse model is the double knockouts (DKO) in which both Abcd1 and Abcd2 transporters are inactivated. The Abcd1-/Abcd2-/-DKO exhibits greater VLCFA accumulation in spinal cord (Pujol et al., 2004), higher levels of oxidative damage to proteins, and a more severe AMN-¬like pathology, with earlier onset of motor impairment than the single Abcd1-null mouse (12 months in the DKO compared to 20 months in Abcd1-null mice). Efficacy of pioglitazone at the motor and neuropathologic levels was studied in 17 Abcd1-/Abcd2-/-mice comparing them with placebo-treated Abcd1-/Abcd2-/-mice (N=17) and wild-type mice (N=25).
In Abcd1-/Abcd2-/-mice treated with pioglitazone at 13 months of age and studied at 15 or 17 months (treatment duration of 2 to 4 months), axonal degeneration was prevented, as shown by the normalization to the control level of number of APP or synaptophysin positive axons.
Also, pioglitazone arrested the progression of locomotor deficits in these mice, as assessed by the treadmill test and the bar-cross test. Indeed, the locomotor performances of pioglitazone DKO after four months of treatment mice reached the performances of the controls.
Overall, these studies show the efficacy of treatment with pioglitazone in "AMN-like mice "and provide a strong rationale for conducting a preliminary open clinical trial with pioglitazone in AMN patients.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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-
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Donostia, Spain, 20080
- Donostia University Hospital
-
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Barcelona
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L'Hospitalet de Llobregat, Barcelona, Spain, 08908
- Bellvitge University Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: XAMNPIO
Pioglitazone 15 mg tablets 2/day during 2 years
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
24 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
24 months
|
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
|
24 months
|
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
|
24 months
|
Sensory disturbances: tactile
Time Frame: 24 months
|
For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)
|
24 months
|
Sensory disturbances: painful
Time Frame: 24 months
|
For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)
|
24 months
|
Sensory disturbances: vibratory
Time Frame: 24 months
|
For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)
|
24 months
|
Expanded disability status scale (EDSS)
Time Frame: 24 months
|
This scale measures motor function, ranging from 0 (normal neurological examination) to 10 (death)
|
24 months
|
Dynamometer test (optional)
Time Frame: 24 months
|
It measures the muscle strength
|
24 months
|
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)
|
24 months
|
SF-Qualiveen
Time Frame: 24 months
|
It measures the impact of urinary disorders in patients with neurological conditions
|
24 months
|
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
|
24 months
|
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.
|
24 months
|
Diffusion tensor Imaging (DTI)
Time Frame: 24 months
|
Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) will be measured
|
24 months
|
Brain MRI spectroscopy (MRS)
Time Frame: 24 months
|
NAA/creatine and choline/creatine ratios will be measured
|
24 months
|
Nerve conduction studies: conduction velocity in the peroneal nerve
Time Frame: 24 months
|
m/s
|
24 months
|
Nerve conduction studies: amplitude of the signal in the peroneal motor nerve
Time Frame: 24 months
|
(mV)
|
24 months
|
Nerve conduction studies: conduction velocity in the sura sensitive nerve
Time Frame: 24 months
|
(m/s)
|
24 months
|
Nerve conduction studies: amplitude of the signal in the sura sensitive nerve
Time Frame: 24 months
|
(μV)
|
24 months
|
Motor Evoked Potentials (MEP): F wave
Time Frame: 24 months
|
(ms) in right and left upper limb and right and left lower limb
|
24 months
|
Motor Evoked Potentials (MEP): Central latency
Time Frame: 24 months
|
(ms) in right and left upper limb and right and left lower limb
|
24 months
|
Motor Evoked Potentials (MEP): Amplitude
Time Frame: 24 months
|
(μV) in right and left upper limb and right and left lower limb
|
24 months
|
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
|
24 months
|
Somatosensory Evoked Potentials (SSEP): Latency N9
Time Frame: 24 months
|
(ms) right and left arms
|
24 months
|
Somatosensory Evoked Potentials (SSEP): Latency N13
Time Frame: 24 months
|
(ms) right and left arms
|
24 months
|
Somatosensory Evoked Potentials (SSEP): Latency N20
Time Frame: 24 months
|
(ms) right and left arms
|
24 months
|
Somatosensory Evoked Potentials (SSEP): Amplitude N20
Time Frame: 24 months
|
(μV) right and left arms
|
24 months
|
Somatosensory Evoked Potentials (SSEP): Latency N8
Time Frame: 24 months
|
(ms) right and left legs
|
24 months
|
Somatosensory Evoked Potentials (SSEP): Latency N22
Time Frame: 24 months
|
(ms) right and left legs
|
24 months
|
Somatosensory Evoked Potentials (SSEP): Latency P40
Time Frame: 24 months
|
(ms) right and left legs
|
24 months
|
Somatosensory Evoked Potentials (SSEP): Amplitude N40
Time Frame: 24 months
|
(μV) right and left legs
|
24 months
|
Brainstem Auditory Evoked Potentials (BAEP): Latency I wave
Time Frame: 24 months
|
(ms) right and left
|
24 months
|
Brainstem Auditory Evoked Potentials (BAEP): Latency III wave
Time Frame: 24 months
|
(ms) right and left
|
24 months
|
Brainstem Auditory Evoked Potentials (BAEP): Latency V wave
Time Frame: 24 months
|
(ms) right and left
|
24 months
|
Brainstem Auditory Evoked Potentials (BAEP): Latency I-III wave
Time Frame: 24 months
|
(ms) right and left
|
24 months
|
Brainstem Auditory Evoked Potentials (BAEP): Latency III-V wave
Time Frame: 24 months
|
(ms) right and left
|
24 months
|
Brainstem Auditory Evoked Potentials (BAEP): Latency I-V wave
Time Frame: 24 months
|
(ms) right and left
|
24 months
|
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
|
24 months
|
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
|
24 months
|
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
|
24 months
|
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
|
24 months
|
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
|
24 months
|
Markers of inflammation: HGF
Time Frame: 24 months
|
HGF will be measured in plasma.
Results will be expressed in pg/ml
|
24 months
|
Markers of inflammation: IL6
Time Frame: 24 months
|
IL6 will be measured in plasma.
Results will be expressed in pg/ml
|
24 months
|
Markers of inflammation: IL8
Time Frame: 24 months
|
IL8 will be measured in plasma.
Results will be expressed in pg/ml
|
24 months
|
Markers of inflammation: MCP-1
Time Frame: 24 months
|
MCP-1 will be measured in plasma.
Results will be expressed in pg/ml
|
24 months
|
Markers of inflammation: NGF
Time Frame: 24 months
|
NGF will be measured in plasma.
Results will be expressed in pg/ml
|
24 months
|
Markers of inflammation: TNF
Time Frame: 24 months
|
TNF will be measured in plasma.
Results will be expressed in pg/ml
|
24 months
|
Markers of inflammation: adiponectin
Time Frame: 24 months
|
Adiponectin will be measured in plasma.
Results will be expressed in μg/ml
|
24 months
|
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
|
24 months
|
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
|
24 months
|
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
|
24 months
|
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
|
24 months
|
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
|
24 months
|
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
|
24 months
|
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
|
24 months
|
Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Metabolic Diseases
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Demyelinating Diseases
- Neurologic Manifestations
- Neurobehavioral Manifestations
- Endocrine System Diseases
- Genetic Diseases, Inborn
- Genetic Diseases, X-Linked
- Metabolism, Inborn Errors
- Mental Retardation, X-Linked
- Intellectual Disability
- Heredodegenerative Disorders, Nervous System
- Brain Diseases, Metabolic
- Brain Diseases, Metabolic, Inborn
- Leukoencephalopathies
- Adrenal Gland Diseases
- Hereditary Central Nervous System Demyelinating Diseases
- Peroxisomal Disorders
- Adrenal Insufficiency
- Adrenoleukodystrophy
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Pioglitazone
Other Study ID Numbers
- XAMNPIOAP2011
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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Viking Therapeutics, Inc.RecruitingAdrenomyeloneuropathy Form (AMN) of X-linked Adrenoleukodystrophy (X-ALD)United States, France, Germany, Italy, United Kingdom
-
MedDay Pharmaceuticals SACompletedAdrenoleukodystrophy | Adrenomyeloneuropathy | AMNFrance, Germany, Spain
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Eunice Kennedy Shriver National Institute of Child...Food and Drug Administration (FDA)TerminatedAdrenoleukodystrophy | AdrenomyeloneuropathyUnited States
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Academisch Medisch Centrum - Universiteit van Amsterdam...The Stop ALD FoundationCompletedAdrenomyeloneuropathy | X-linked AdrenoleukodystrophyNetherlands
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Poxel SANot yet recruiting
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Onofre, Aurora Pujol, M.D.Completed
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Assistance Publique - Hôpitaux de ParisRecruitingAdrenoleukodystrophy | Adrenomyeloneuropathy | Metachromatic Leukodystrophy | Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented GliaFrance
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