E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis |
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E.1.1.1 | Medical condition in easily understood language |
Amyotrophic Lateral Sclerosis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002026 |
E.1.2 | Term | Amyotrophic lateral sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
To determine the efficacy of chronic treatment with arimoclomol 1200 mg/day (400 mg TID) compared to placebo over 76 weeks in subjects with ALS as assessed with Combined Assessment of Function and Survival (CAFS) |
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E.2.2 | Secondary objectives of the trial |
To evaluate the impact of arimoclomol 1200 mg/day (400 mg TID) compared to placebo on:
• Time to permanent assisted ventilation (PAV)/tracheostomy free survival
• Disease progression as measured by change from Baseline of the ALSFRS-R
• Progression of respiratory dysfunction as measured by change from Baseline of the slow vital capacity (SVC)
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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 Muscle-strength and Electromyography testing. Muscle-strength
and Electromyography will be measured in a sub-study conducted in
approximately 40 subjects at selected trial sites. Electrophysiology and
muscle-strength testing will be performed in the same subset of subjects
at the following in-person visits; Baseline, Week 20, Week 52 and Week
76 (or end of trial). The assessments will only be performed if
appropriate in the opinion of the investigator. Subjects will signed a
separate consent form indicating their willingness to have this testing. |
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E.3 | Principal inclusion criteria |
1. Capable of- and willing to- provide written informed consent and comply with trial procedures.
2. Subject is male or female ≥18 years of age.
3. Subject meets revised El Escorial criteria for clinically possible, clinically probable / clinically probable ALS laboratory-supported or clinically definite ALS, or familial ALS laboratory-supported.
4. 18 months or less since first appearance of weakness (e.g. limb weakness, dysarthria, dysphagia, shortness of breath).
5. ALSFRS-R ≥35 and erect (seated) SVC % predicted ≥ 70% at Screening.
6. Able and willing to travel to the site, and in the investigator’s opinion is likely to attend visits for at least 24 weeks.
7. All sexually active female subjects of child-bearing potential (postmenarchal)* must agree not to intend to become pregnant and use a highly effective method of contraception** during the trial through 1 week after the last dose of trial medication. If the subject is a sexually active male with female partners of child-bearing potential (postmenarchal) he must use a condom with or without spermicide in addition to the birth control used by their partners during the trial until 3 months after the last dose of trial medication.
8. Stable dose of riluzole (50 mg twice daily) for a minimum of 14 days prior to Day 1 (Baseline), or has not taken it for 14 days prior to Day 1. |
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E.4 | Principal exclusion criteria |
1. Tracheostomy or use of non-invasive ventilation for more than 2 hours during waking hours at the time of Screening and Baseline visits.
2. Pregnant or breast-feeding.
3. Current or anticipated use of diaphragmatic pacing during the trial.
4. Exposure to any investigational treatment within 4 weeks or <5 halflives of the Screening visit, whichever is longest and/or advanced therapy medicinal product (ATMP), i.e. treatments based on genes, cells or tissues and/or participated in any prior ALS clinical trial receiving active drug treatment (with the exception described in exclusion criterion 5).
5.Treatment with edaravone within 4 weeks of the Baseline visit.
Previously or currently treated with edaravone. However, up to 18 subjects on stable (i.e. minimum 6 months’) treatment with edaravone and who otherwise fulfil the eligibility criteria are planned for enrolment (limited to countries where edavarone has a marketing authorisation for treatment of ALS).
6. Any of the following medically significant conditions:
a) Neurological impairment/dysfunction or unstable psychiatric illness that in the investigator’s opinion is likely to interfere with assessment of ALS disease progression.
b) Clinically significant unstable medical condition other than ALS, which would present a risk to a subject to participate in the trial
c) Presence of dementia that impairs the ability of the subject to provide informed consent according to the PI decision.
d) Known or suspected allergy or intolerance to the IMP (arimoclomol or constituents);
e) Chronic infection particularly HIV or Hepatitis B or C.
f) Clinically significant renal or hepatic disease
g) Aspartate aminotransferase and/or alanine aminotransferase, and/or lactate dehydrogenase ≥3 times the upper limit of normal [ULN], bilirubin≥2 times the ULN, or creatinine ≥1.5 times the ULN). Laboratory tests may be repeated once at Screening. Reasons to repeat laboratory tests may include that the medication causing laboratory abnormality was suspended, any other suspected cause may no longer exist, or to rule out laboratory error.
h) Cancer that is currently under active treatment or is likely to require treatment during the trial that may alter the subject´s function and thereby interfere with assessment of ALS disease progression.
i) Any other condition that in the investigator’s opinion would present a risk to a subject to participate in the trial, interfere with the assessment of safety or has an increased risk of causing death during the trial.
* Non child-bearing potential is defined as post-menopausal (minimum of 12 months with no menses and follicle-stimulating hormone in the post-menopausal range) or sterilisation (hysterectomy, oophorectomy, or bilateral tubal ligation).
** Highly effective methods of contraception include combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; and vasectomised partner.
According to the recommendations from the Clinical Trial Facilitation Group (CTFG, 2014), sexual abstinence is considered a highly effective birth control method only if it is defined as refraining from heterosexual intercourse during the trial until 1 week after the last dose of trial medication (for female subjects of child-bearing potential) and for 3 months after the last dose of trial medication (for male subjects with female partners of child-bearing potential). The reliability of sexual abstinence needs to be evaluated by the investigator in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
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E.5 End points |
E.5.1 | Primary end point(s) |
Combined assessment of function and survival (CAFS) over a treatment period of 76 weeks (or end-of-trial) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
76 weeks (or end-of-trial) |
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E.5.2 | Secondary end point(s) |
• Time to PAV/tracheostomy/death
• Change from Baseline to Week 76 (or end-of-trial) in ALSFRS-R
• Change from Baseline to Week 76 (or end-of-trial) in SVC
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
76 weeks (or end-of-trial) |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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) | No |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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 | 16 |
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 |
Belgium |
Canada |
France |
Germany |
Italy |
Netherlands |
Poland |
Spain |
Sweden |
Switzerland |
United Kingdom |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |