AdrenomyeloneuropathyPhase 2XAMNPIOP2011NCT03864523
Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy
A Phase 2 study testing Pioglitazone in people with Adrenomyeloneuropathy and X-linked Adrenoleukodystrophy, run by Pujol, Aurora, M.D. at 2 sites in Spain.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Adrenomyeloneuropathy, X-linked Adrenoleukodystrophy
- What is being tested?
- Pioglitazone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 2 sitesSpain
- Study dates
- Jan 2016to Jul 2019
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 12Show fewer
- 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
Who cannot join
- 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
Show all 31Show fewer
- 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
Trial locations and contacts
2 sites in 1 country.
Spain2 sites
Donostia University Hospital
Donostia / San Sebastian, 20080
Bellvitge University Hospital
L'Hospitalet de Llobregat, Barcelona, 08908
About this study
Official title: 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.
Read the 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.
- Being tested
- Pioglitazone
- Keywords
- AMN, pioglitazone
- Medical subject headings
- Adrenoleukodystrophy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PioglitazoneDrug
| Study group | Role | What they receive |
|---|---|---|
| XAMNPIO | Experimental | Pioglitazone 15 mg tablets 2/day during 2 years Receives: Drug: Pioglitazone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 24 months
Secondary outcomes (55)
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
Measured: 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
Measured: 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
Measured: 24 months
Sensory disturbances: tactile
For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)
Measured: 24 months
Sensory disturbances: painful
For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)
Measured: 24 months
Sensory disturbances: vibratory
For the evaluation the Total Neuropathy Score (TNS) will be used (0-4)
Measured: 24 months
Expanded disability status scale (EDSS)
This scale measures motor function, ranging from 0 (normal neurological examination) to 10 (death)
Measured: 24 months
Dynamometer test (optional)
It measures the muscle strength
Measured: 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)
Measured: 24 months
SF-Qualiveen
It measures the impact of urinary disorders in patients with neurological conditions
Measured: 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
Measured: 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.
Measured: 24 months
Diffusion tensor Imaging (DTI)
Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) will be measured
Measured: 24 months
Brain MRI spectroscopy (MRS)
NAA/creatine and choline/creatine ratios will be measured
Measured: 24 months
Nerve conduction studies: conduction velocity in the peroneal nerve
m/s
Measured: 24 months
Nerve conduction studies: amplitude of the signal in the peroneal motor nerve
(mV)
Measured: 24 months
Nerve conduction studies: conduction velocity in the sura sensitive nerve
(m/s)
Measured: 24 months
Nerve conduction studies: amplitude of the signal in the sura sensitive nerve
(μV)
Measured: 24 months
Motor Evoked Potentials (MEP): F wave
(ms) in right and left upper limb and right and left lower limb
Measured: 24 months
Motor Evoked Potentials (MEP): Central latency
(ms) in right and left upper limb and right and left lower limb
Measured: 24 months
Motor Evoked Potentials (MEP): Amplitude
(μV) in right and left upper limb and right and left lower limb
Measured: 24 months
Motor Evoked Potentials (MEP): Central motor conduction time
(ms) in right and left upper limb and right and left lower limb
Measured: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N9
(ms) right and left arms
Measured: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N13
(ms) right and left arms
Measured: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N20
(ms) right and left arms
Measured: 24 months
Somatosensory Evoked Potentials (SSEP): Amplitude N20
(μV) right and left arms
Measured: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N8
(ms) right and left legs
Measured: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N22
(ms) right and left legs
Measured: 24 months
Somatosensory Evoked Potentials (SSEP): Latency P40
(ms) right and left legs
Measured: 24 months
Somatosensory Evoked Potentials (SSEP): Amplitude N40
(μV) right and left legs
Measured: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency I wave
(ms) right and left
Measured: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency III wave
(ms) right and left
Measured: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency V wave
(ms) right and left
Measured: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency I-III wave
(ms) right and left
Measured: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency III-V wave
(ms) right and left
Measured: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency I-V wave
(ms) right and left
Measured: 24 months
Markers of oxidative stress: GSA
Glutamic semialdehyde (GSA) will be measured in plasma. Results will be expressed in μmol/mol lysine
Measured: 24 months
Markers of oxidative stress: CEL
Carboxyethyl-lysine (CEL) will be measured in plasma. Results will be expressed in μmol/mol lysine
Measured: 24 months
Markers of oxidative stress: MDAL
N2-malondialdehyde-lysine (MDAL) will be measured in plasma. Results will be expressed in μmol/mol lysine
Measured: 24 months
Markers of oxidative stress: CML
N2-carboxymethyl-lysine (CML) will be measured in plasma. Results will be expressed in μmol/mol lysine
Measured: 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
Measured: 24 months
Markers of inflammation: HGF
HGF will be measured in plasma. Results will be expressed in pg/ml
Measured: 24 months
Markers of inflammation: IL6
IL6 will be measured in plasma. Results will be expressed in pg/ml
Measured: 24 months
Markers of inflammation: IL8
IL8 will be measured in plasma. Results will be expressed in pg/ml
Measured: 24 months
Markers of inflammation: MCP-1
MCP-1 will be measured in plasma. Results will be expressed in pg/ml
Measured: 24 months
Markers of inflammation: NGF
NGF will be measured in plasma. Results will be expressed in pg/ml
Measured: 24 months
Markers of inflammation: TNF
TNF will be measured in plasma. Results will be expressed in pg/ml
Measured: 24 months
Markers of inflammation: adiponectin
Adiponectin will be measured in plasma. Results will be expressed in μg/ml
Measured: 24 months
Markers of inflammation: CCR3
CCR3 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Measured: 24 months
Markers of inflammation: CXCL5
CXCL5 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Measured: 24 months
Markers of inflammation: CXCL9
CXCL9 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Measured: 24 months
Markers of inflammation: IL9R
IL9R will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Measured: 24 months
Markers of inflammation: PPARd
PPARd will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Measured: 24 months
Markers of inflammation: GPX4
GPX4 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Measured: 24 months
Markers of inflammation: STAT1
STAT1 will be measured in RNA from peripheral mononuclear cells. Results will be expressed as relative gene expression
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Mar 2019
- Study startJan 2016
- Primary completionMar 2019
- Study completionJul 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AdrenomyeloneuropathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Pujol, Aurora, M.D.
- Collaborators
- Instituto de Salud Carlos III, Fundacion Hesperia, ELA España Association
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03864523
- Sponsor's protocol ID
- XAMNPIOAP2011
- Acronym
- XAMNPIOP2011
- Status last verified
- Mar 2019
- First submitted
- 16 Sep 2016
- Last updated
- 10 Sep 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy: a Phase II, Single-arm, Multicentric Clinical Trial
- ClinicalTrials.gov ID
- NCT03864523
- Acronym / sponsor ID
- XAMNPIOP2011 / XAMNPIOAP2011
- Keywords
- AMN, pioglitazone
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Pujol, Aurora, M.D.
- Collaborators
- Instituto de Salud Carlos III, Fundacion Hesperia, ELA España Association
- Study start
- Jan 2016
- Primary completion
- Mar 2019 (actual)
- Study completion
- Jul 2019 (actual)
- First posted
- 6 Mar 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| XAMNPIO | Experimental | Drug: PioglitazonePioglitazone 15 mg tablets 2/day during 2 years |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (31 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pioglitazone | Drug | XAMNPIO |
Primary outcome
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
55 secondary outcomes
Timed Up and Go (TUG) test
Time frame: 24 months
Time to walk 25 Feet (TW25)
Time frame: 24 months
6 Minute Walk Test (6MWT)
Time frame: 24 months
Sensory disturbances: tactile
Time frame: 24 months
Sensory disturbances: painful
Time frame: 24 months
Sensory disturbances: vibratory
Time frame: 24 months
Expanded disability status scale (EDSS)
Time frame: 24 months
Dynamometer test (optional)
Time frame: 24 months
Ashworth scale
Time frame: 24 months
SF-Qualiveen
Time frame: 24 months
Revised Faecal Incontinence Scale (RFIS)
Time frame: 24 months
Conventional MRI
Time frame: 24 months
Diffusion tensor Imaging (DTI)
Time frame: 24 months
Brain MRI spectroscopy (MRS)
Time frame: 24 months
Nerve conduction studies: conduction velocity in the peroneal nerve
Time frame: 24 months
Nerve conduction studies: amplitude of the signal in the peroneal motor nerve
Time frame: 24 months
Nerve conduction studies: conduction velocity in the sura sensitive nerve
Time frame: 24 months
Nerve conduction studies: amplitude of the signal in the sura sensitive nerve
Time frame: 24 months
Motor Evoked Potentials (MEP): F wave
Time frame: 24 months
Motor Evoked Potentials (MEP): Central latency
Time frame: 24 months
Motor Evoked Potentials (MEP): Amplitude
Time frame: 24 months
Motor Evoked Potentials (MEP): Central motor conduction time
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N9
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N13
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N20
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Amplitude N20
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N8
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency N22
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Latency P40
Time frame: 24 months
Somatosensory Evoked Potentials (SSEP): Amplitude N40
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency I wave
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency III wave
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency V wave
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency I-III wave
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency III-V wave
Time frame: 24 months
Brainstem Auditory Evoked Potentials (BAEP): Latency I-V wave
Time frame: 24 months
Markers of oxidative stress: GSA
Time frame: 24 months
Markers of oxidative stress: CEL
Time frame: 24 months
Markers of oxidative stress: MDAL
Time frame: 24 months
Markers of oxidative stress: CML
Time frame: 24 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Sep 2019.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pioglitazone in people with Adrenomyeloneuropathy and X-linked Adrenoleukodystrophy, run by Pujol, Aurora, M.D. at 2 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
2 Minute Walk Test (2MWT) (time frame: 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Sep 2019.