| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Amyotrophic Lateral Sclerosis (ALS) |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10002026 |
| E.1.2 | Term | Amyotrophic lateral sclerosis |
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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 assess whether lithium carbonate, in doses achieving blood levels of 0.4-0.8mmols/L, significantly prolongs survival in ALS over 18 months, without clinically significant safety toxicity. |
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| E.2.2 | Secondary objectives of the trial |
To assess whether treatment with lithium carbonate slows the rate of functional deterioration over 18 months.
To assess whether treatment with lithium carbonate affects quality of life or mental state in ALS patients. |
|
| 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 |
Open Label Extension (as detailed in LiCALS protocol version 7 dated 2nd August 2010)
Surviving blinded participants who have completed their month 18 visit and who have been on continuous trial medications will be asked whether they would like to participant in an open label extension. Participants must meet the inclusion/ exclusion criteria detailed below.
The number of patients to be recruited at each of the centres will be based on the number of participants recruited to the double blind section of the study.
Objective
• To obtain further evidence of the safety of lithium carbonate (LiCO3), in doses achieving blood levels of 0.4-0.8 mmols/L.
Outcome
• Safety monitoring only
• Survival status
Inclusion criteria
1. Participants who have completed week 77 of the LICALS double blind trial.
2. Age: ≥18 years (inclusive).
3. In the case of a female with childbearing potential, the patient must not be pregnant or breast-feeding. Women of childbearing potential will have a urine pregnancy test before randomisation; and at each clinic visit. The results of those must be negative. Women of childbearing potential should use adequate contraception.
4. Capable of understanding the information given and giving fully informed consent prior to any study specific procedures.
Exclusion criteria
1. Any laboratory abnormal values considered by the local physician to contraindicate lithium.
2. Recorded diagnosis or evidence of major psychiatric disorder or clinically evident dementia.
3. Known allergy or hypersensitivity to lithium, or its excipients.
4. Likely to be uncooperative or to fail to comply with the trial requirements or to be inaccessible in the event of an emergency.
5. Subjects with significant haematological, biochemical and autoimmune abnormalities, as judged by the study physician.
6. If a woman of childbearing potential, unable or unwilling to use effective contraception during the study.
7. Patients already taking lithium in any form outside the LICALS trial.
8. Presence of a medical condition contra-indicative to the use of lithium, according to the BNF (http://www.bnf.org/bnf/)
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|
| E.3 | Principal inclusion criteria |
• Patients with Possible, Laboratory-supported Probable, Probable or Definite ALS according to the revised version of the El Escorial World Federation of Neurology criteria (The ‘Airlie House Statement’: http://www.wfnals.org)
These criteria are internationally accepted research diagnostic criteria with high specificity and sensitivity. The onset form (bulbar or limb) and disease type (familial or sporadic) will be recorded; source documents will include a full report of an electromyogram (EMG) reported by an experienced neurophysiologist as compatible with ALS.
• Disease duration ≥6 months and ≤36 calendar months (inclusive), with disease onset defined as date of first muscle weakness, or dysarthria.
• FVC ≥60% of predicted within 1 month prior to randomisation
• Age: ≥18 years (inclusive).
• In the case of a female with childbearing potential, the patient must not be pregnant or breast-feeding. Women of childbearing potential will have a urine pregnancy test before randomisation; and at each clinic visit. The results of those must be negative. Women of childbearing potential should use two barrier methods of contraception.
• Continuously treated with riluzole for at least 4 weeks prior to screening (28 days inclusive) and stabilised at 100 mg/day (50 mg bid) without significant adverse drug reactions.
• Capable of understanding the information given and giving fully informed consent prior to any study specific procedures.
|
|
| E.4 | Principal exclusion criteria |
• Participation in another therapeutic study within the preceding 12 weeks or use of other investigational drugs or agents.
• Tracheostomy, or assisted ventilation of any type during the preceding three months.
• Existing gastrostomy, unless elective and not currently used for nutritional support or hydration.
• Any medical condition known to have an association with motor neuron dysfunction which might confound or obscure the diagnosis of ALS.
• Presence of any concomitant life-threatening disease or any disease or impairment likely to interfere with functional assessment.
• Confirmed hepatic insufficiency or abnormal liver function (ALT greater than 1.5 the upper limit of the normal range) within one month of randomisation. That blood test may be repeated in the case of initial abnormal results; if the AST and ALT return to normal, the patient may then be included in the study.
• Renal insufficiency (serum creatinine >200 µmol/L [2.26 mg/dL]) within one month of randomisation. That blood test may be repeated in the case of initial abnormal results; if the AST and ALT return to normal, the patient may then be included in the study.
• Recorded diagnosis or evidence of major psychiatric disorder or clinically evident dementia.
• Known allergy or hypersensitivity to lithium, or its excipients.
• Likely to be uncooperative or to fail to comply with the trial requirements or to be inaccessible in the event of an emergency.
• Subjects with significant haematological, biochemical and autoimmune abnormalities, as judged by the study physician.
• If a woman of childbearing potential, unable or unwilling to use effective contraception (two barrier methods) during the study.
• Patients with active inflammation/infection at screening or Baseline (Day 0). Patients presenting with active inflammation/infection can be reassessed at a later date, and included in the trial if the infection/inflammation has cleared.
• Patients already taking lithium in any form.
• Presence of a medical condition contra-indicative to the use of lithium, according to the BNF (http://www.bnf.org/bnf/)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Survival at 18 months from randomisation. The outcome measure therefore is death from any cause.
|
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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 | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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