A Phase 2 interventional study of Pioglitazone in Adrenomyeloneuropathy and X-linked Adrenoleukodystrophy, sponsored by Pujol, Aurora, M.D.. Completed at 2 sites in Spain. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2019-09-10.
Sponsored by Pujol, Aurora, M.D. · Phase 2, Interventional, and Treatment
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.
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.
68 studies on the registry are indexed under Adrenoleukodystrophy; 19 are open to participants now.
This study's enrollment of 18 is below the median of 31 across 40 interventional studies indexed under Adrenoleukodystrophy.
Browse Adrenoleukodystrophy studies →Pujol, Aurora, M.D. is the lead sponsor of 4 studies on the registry; none are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
LVEF (left ventricular ejection fraction)
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECG (electrocardiogram)
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
NYHA class (heart failure)
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Excipients
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Pioglitazone 15 mg tablets 2/day during 2 years
Drug: Pioglitazone
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
Time frame: 24 months
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
Time frame: 24 months
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
Time frame: 24 months
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
Time frame: 24 months
Sensory disturbances: tactile
For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)
Time frame: 24 months
Sensory disturbances: painful
For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)
Time frame: 24 months
Sensory disturbances: vibratory
For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)
Time frame: 24 months
Expanded disability status scale (EDSS)
This scale measures motor function, ranging from 0 (normal neurological examination) to 10 (death)
Time frame: 24 months
Dynamometer test (optional)
It measures the muscle strength
Time frame: 24 months
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)
Time frame: 24 months
SF-Qualiveen
It measures the impact of urinary disorders in patients with neurological conditions
Time frame: 24 months
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
Time frame: 24 months
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.
Time frame: 24 months
Diffusion tensor Imaging (DTI)
Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) will be measured
Time frame: 24 months
Brain MRI spectroscopy (MRS)
NAA/creatine and choline/creatine ratios will be measured
Time frame: 24 months
Nerve conduction studies: conduction velocity in the peroneal nerve
m/s
Time frame: 24 months
Nerve conduction studies: amplitude of the signal in the peroneal motor nerve
(mV)
Time frame: 24 months
Nerve conduction studies: conduction velocity in the sura sensitive nerve
(m/s)
Time frame: 24 months
Nerve conduction studies: amplitude of the signal in the sura sensitive nerve
(μV)
Time frame: 24 months
Motor Evoked Potentials (MEP): F wave
(ms) in right and left upper limb and right and left lower limb
Time frame: 24 months
Motor Evoked Potentials (MEP): Central latency
(ms) in right and left upper limb and right and left lower limb
Time frame: 24 months
Motor Evoked Potentials (MEP): Amplitude
(μV) in right and left upper limb and right and left lower limb
Time frame: 24 months
Motor Evoked Potentials (MEP): Central motor conduction time
(ms) in right and left upper limb and right and left lower limb
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N9
(ms) right and left arms
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N13
(ms) right and left arms
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N20
(ms) right and left arms
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Amplitude N20
(μV) right and left arms
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N8
(ms) right and left legs
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N22
(ms) right and left legs
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency P40
(ms) right and left legs
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Amplitude N40
(μV) right and left legs
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency I wave
(ms) right and left
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency III wave
(ms) right and left
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency V wave
(ms) right and left
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency I-III wave
(ms) right and left
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency III-V wave
(ms) right and left
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency I-V wave
(ms) right and left
Time frame: 24 months
Markers of oxidative stress: GSA
Glutamic semialdehyde (GSA) will be measured in plasma. Results will be expressed in μmol/mol lysine
Time frame: 24 months
Markers of oxidative stress: CEL
Carboxyethyl-lysine (CEL) will be measured in plasma. Results will be expressed in μmol/mol lysine
Time frame: 24 months
Markers of oxidative stress: MDAL
N2-malondialdehyde-lysine (MDAL) will be measured in plasma. Results will be expressed in μmol/mol lysine
Time frame: 24 months
Markers of oxidative stress: CML
N2-carboxymethyl-lysine (CML) will be measured in plasma. Results will be expressed in μmol/mol lysine
Time frame: 24 months
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
Time frame: 24 months
Markers of inflammation: HGF
HGF will be measured in plasma. Results will be expressed in pg/ml
Time frame: 24 months
Markers of inflammation: IL6
IL6 will be measured in plasma. Results will be expressed in pg/ml
Time frame: 24 months
Markers of inflammation: IL8
IL8 will be measured in plasma. Results will be expressed in pg/ml
Time frame: 24 months
Markers of inflammation: MCP-1
MCP-1 will be measured in plasma. Results will be expressed in pg/ml
Time frame: 24 months
Markers of inflammation: NGF
NGF will be measured in plasma. Results will be expressed in pg/ml
Time frame: 24 months
Markers of inflammation: TNF
TNF will be measured in plasma. Results will be expressed in pg/ml
Time frame: 24 months
Markers of inflammation: adiponectin
Adiponectin will be measured in plasma. Results will be expressed in μg/ml
Time frame: 24 months
Markers of inflammation: CCR3
CCR3 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Time frame: 24 months
Markers of inflammation: CXCL5
CXCL5 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Time frame: 24 months
Markers of inflammation: CXCL9
CXCL9 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Time frame: 24 months
Markers of inflammation: IL9R
IL9R will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Time frame: 24 months
Markers of inflammation: PPARd
PPARd will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Time frame: 24 months
Markers of inflammation: GPX4
GPX4 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Time frame: 24 months
Markers of inflammation: STAT1
STAT1 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Time frame: 24 months
Plan to share: No
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This study is completed, as verified in Mar 2019. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Pioglitazone
Pujol, Aurora, M.D.