E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ADRENOMYELONEUROPATHY IN MALE PATIENTS WITH X-LINKED ADRENOLEUKODYSTROPHY |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Main Study: Efficacy of MIN-102 on the progression of adrenomyeloneuropathy (AMN) in male patients as determined by the change from baseline in Six-Minute Walk Test (6MWT) compared with placebo after 96 weeks of treatment.
Extension Study: To assess the safety and tolerability of MIN-102 upon long-term treatment. |
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E.2.2 | Secondary objectives of the trial |
Main Study: To evaluate the effects of MIN-102 after 96 weeks of treatment on: • Change from baseline in body sway amplitude (in four states: eyes closed/feet apart, eyes open/feet apart, eyes closed/feet together, eyes open/feet together) • Comprehensive clinical rating scales (Severity Score System for Progressive Myelopathy [SSPROM] and Expanded Disability Status Scale [EDSS]) • Clinician and patient global impression of symptom severity and change • Muscle strength • Quality of life • Incidence of progression of cerebral lesions. • Loes severity score
Extension Study: Secondary objectives- To evaluate the long-term effects of MIN-102 on: • Change from baseline in 6MWT and body sway (in four states: eyes closed/feet apart, eyes open/feet apart, eyes closed/feet together, eyes open/feet together) • Comprehensive clinical rating scales (SSPROM and EDSS) • Quality of life • Incidence of progression of cerebral lesions.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional CSF Sampling Sub-Study (integral part of Protocol Version 2.0 dated 05 Oct 2017) Objective: To evaluate the effects of MIN-102 on various biochemical markers in plasma and cerebrospinal fluid (CSF).
Optional Spinal Cord MRI scan Sub-study (integral part of Protocol Version 2.0 dated 05 Oct 2017) Objective: To evaluate the effects of MIN-102 on spinal cord imaging parameters.
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E.3 | Principal inclusion criteria |
Main Study:
1. Provision of written informed consent to participate in the main study. 2. Male patients aged ≥18 to ≤65 years. 3. Diagnosis of ALD based on genetic testing. 4. Clinical evidence of spinal cord involvement, with an EDSS score between 2 and 6. 5. Ability to walk for 6 minutes, without or with rest, with usual walking aids (e.g. lag braces, cane or crutch). 6. Ability to stand on a force plate with closed eyes and with feet apart for a minimum of 20 seconds. 7. Either a normal brain MRI or a type-1 through type-5 pattern MRI abnormality in which the abnormality does not show presence of inflammation. Note: MRI is not required at V-1 if an MRI was obtained within the 6 months prior to the first day of screening. 8. Normal adrenal function or appropriate steroid replacement if adrenal insufficiency is present. 9. Patients who are surgically sterilized. If not surgically sterilized, patients should be willing to use adequate contraception and not donate sperm from the first dose of the study medication until 90 days after the follow-up visit. Adequate contraception for the male patient (and his female partner, if of childbearing potential) is defined as hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. Total abstinence, in accordance with the lifestyle of the patient, is also acceptable.
Extension Study: 1. Completion of the entire 96-weeks double-blind period of the study (Part 1). 2. Provision of written informed consent to participate in the extension study part. 3. Normal adrenal function or appropriate steroid replacement if adrenal function has changed during the double-blind treatment phase. 4. The following inclusion criteria of Part 1 will be modified: • age ≥18 to ≤65 years will no longer apply. • EDSS score between 2 and 6 will no longer apply. • Ability to walk for 6 minutes will no longer apply. If a patient is unable to walk for 6 minutes, the maximum time and walking distance will be recorded. If a patient is unable or refuses to walk at all, this will also be recorded. • Ability to stand on a force plate with eyes closed and feet apart for a minimum of 20 seconds will no longer apply. If a patient is no longer able to stand on a force plate for 20 seconds, this test will not be conducted. • Either a normal brain MRI or a type-1 through type-5 pattern MRI abnormality in which the abnormality does not show presence of inflammation (gadolinium enhancement) will no longer apply. In case of brain MRI lesions making the patient eligible for HSCT, he is still eligible for the extension study, but treatment will be discontinued immediately before any transplant-related treatment is initiated. A stable dose of Lorenzo's Oil, botulinum toxin, N-acetylcysteine, baclofen, benzodiazepines, opiates and cannabis preparations, fampidrine and antioxidants will no longer apply. All other inclusion criteria of Part 1 remain in place.
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E.4 | Principal exclusion criteria |
Main Study & Extension Study: 1. Any other chronic neurological disease with signs of spastic paraplegia 2. Known type 1 or type 2 diabetes. 3. Known intolerance to pioglitazone or any other thiazolidinedione. 4. Current treatment with immunosuppressant medication, except for corticosteroids. 5. Previous or current history of cancer, bone marrow transplantation, Congestive heart failure, significant liver and renal disorders, anemia, pulmonary or cardiac diseases, Cognitive or behavioral abnormalities, alcohol/drug abuse etc. 6. Reduced left-ventricular ejection fraction, or other clinically significant cardiac abnormalities on echocardiogram that in the investigator´s opinion could predispose the subject to volume overload or its attendant consequences. 7. A positive result on laboratory tests for hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus antibody.
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E.5 End points |
E.5.1 | Primary end point(s) |
Main Study: 1. Efficacy: Change from baseline to week 96 in the total walking distance in the 6MWT
Extension Study: 1. Long-term safety and tolerability assessed in terms of AE, SAE, SUSARs, Vitals signs, ECG, Clinical Laboratory tests |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Main Study:Secondary efficacy endpoints are changes from baseline to week 96 in the following: • Body sway amplitude (in four states: eyes closed/feet apart, eyes open/feet apart, eyes closed/feet together, eyes open/feet together) • SSPROM • EDSS • Clinical Global Impressions - Severity (CGI-S) • Clinical Global Impressions - Improvement (CGI-I) • Patient Global Impressions - Improvement (PGI-I) • Dynamometry • Quality of Life Assessments - European Quality of Life 5 Dimensions (EQ-5D-5L) - Multiple Sclerosis Walking Scale (MSWS-12) - Qualiveen Short Form quality of life questionnaire for urinary disorders (Qualiveen-SF) - International Index of Erectile Function questionnaire (IIEF) • Cerebral MRI (incidence of inflammatory lesions).
Extension Study: The efficacy endpoints are the changes from the baseline of Part 2 (V6) to the last scheduled on-study assessment for the following variables: • 6MWT • Body sway amplitude (in four states: eyes closed/feet apart, eyes open/feet apart, eyes closed/feet together, eyes open/feet together) • SSPROM • EDSS • Quality of Life Assessments (EQ-5D-5L, MSWS-12, Qualiveen-SF and IIEF). • Cerebral MRI (incidence of inflammatory lesions).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Main Study is Randomized, Controlled, Double-Blind and Extension Study is Open-Label |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
France |
Germany |
Hungary |
Italy |
Netherlands |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Main Study: LVLS (expected duration of trial is 3 years after which Clinical Study Report (CSR) will be written)
Extension Study: LVLS (expected duration of trial cannot be estimated since it will be for unlimited time in principle) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |