E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis (ALS) |
Amyotrofisk lateralskleros (ALS) |
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E.1.1.1 | Medical condition in easily understood language |
A progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord further affecting motor neurons. Motor neurons die leading to loss of muscle control and function. |
En progressiv neurodegenerativ sjukdom som påverkar nervceller i hjärna och ryggmärg som vidare påverkar motorneuron. Motorneuronen dör vilket leder till förlust av muskelkontroll och muskelfunktion. |
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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 | 17.0 |
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 |
SAFETY OBJECTIVE
To investigate the safety and tolerability of the combination therapy of Apovir in patients with ALS
PRIMARY EFFICACY OBJECTIVE
To investigate the effect of Apovir on 12-months disease progression of ALS as assessed by ALSFRS-R score from baseline compared to placebo
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E.2.2 | Secondary objectives of the trial |
SECONDARY EFFICACY OBJECTIVES
To investigate the effect of Apovir on disease progression of ALS assessed by ALSFRS-R score at the 4-weeks, 3-, 6-, 9-months, and Follow-up visits, and forced vital capacity (FVC), vital capacity (VC) and maximal voluntary ventilation (MVV) at the 4-weeks, 3-, 6-, 9-, 12-months, and Follow-up visits
To investigate the combined effect of Apovir on ALSFRS-R, and death or the use of definitive life supporting breathing assistance and death as assessed by Combined assessment of function and survival (CAFS) at the 4-weeks, 3-, 6-, 9-, 12-months, and follow-up visits
To investigate the effect of Apovir on time from onset of ALS symptoms to the use of definitive life supporting breathing assistance, or Death
To investigate the plasma concentrations of Apovir in patients with ALS
Refer to the protocol for further secondary objectives.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female study subjects fulfilling the probable or higher criteria for ALS according to the revised El-Escorial criteria
2. First documented symptom of ALS ≤ 24 months before screening
3. The sum of the 3 respiratory items on the ALSFRS-R, 10: dyspnoea, 11: orthopnoea and 12: respiratory insufficiency, must total at least 10 points
4. Ability to walk without other walking aids than a crutch
5. 18 – 80 years at the time of screening
6. FEV% ≥70%
7. Study subjects with or without pharmacological treatment, i.e. Riluzole for ALS (study subjects with ongoing pharmacological treatment for ALS shall have received unchanged treatment as regards drug(s) and dose(s) for at least 1 month)
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E.4 | Principal exclusion criteria |
1. Women in fertile age with a positive pregnancy blood test, or planning to become pregnant during the period of the trial. Fertile women include any female who has experienced menarche, who has not undergone tubal ligation, and who is not postmenopausal. Postmenopausal is defined as amenorrhea ≥ 12 consecutive months without another cause
2. Sexually active men and women without highly effective contraceptive treatment, e.g. sterilisation, condoms and diaphragms with spermicide; oral contraceptives (including Progesterone-only pills in high dose) in combination with a barrier method; hormonal contraceptives alone are not sufficient
3. Active hepatitis B, active hepatitis C, or HIV infection
4. Serious cardiac disease including unstable or uncontrolled cardiac disease during the last 6 months and/or a previous history or present clinical signs of deep venous thrombosis
5. Major surgical procedure within 4 weeks prior to start of treatment
6. Participation in any other clinical trial within 30 days of inclusion (randomisation) in the trial or patients with unresolved investigational treatment-related adverse events
7. Other chronic disease or previous organ transplantation judged by the Investigator to interfere with the assessment of treatment success and/or ability to fully participate in the trial
8. Impaired kidney function with an absolute GFR calculated from cystatin C <60 mL/min
9. Known blood disease or Anaemia Haemoglobin <120 g/L for women and <130 g/L for men
10. Known haemoglobinopathy (e.g. thalassemia and sickle cell anaemia)
11. Patients that require immunosuppressive treatments including azathioprine, cyclosporine, systemic steroid treatment (e.g. prednisolone at doses of ≥10 mg/day or hydrocortisone) or has received such treatment within the last 6 months prior to randomization
12. Patients that are treated with drugs that can interact significantly with APO-P001; ethinylestradiol and/or ribavirin; azathioprine, didanosine, zidovudine, mercaptopurine, stavudine
13. Lack of suitability for participation in the trial, for any reason, as judged by the Investigator
14. Patients with clinical or other signs of frontal temporal lobe dementia (FTLD) or known heredity for FTLD |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Safety Endpoint
• Frequency and intensity of adverse events
Primary efficacy Endpoints
• Change in ALSFRS-R from baseline to 12 months using mean change of slope
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Safety Endpoint
Evaluations will be analysed throughout the whole CT.
Primary efficacy Endpoints
12 months |
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E.5.2 | Secondary end point(s) |
Change in disease progression of ALS as assessed by:
• Change in ALSFRS-R score from baseline to the 4-weeks, 3-, 6-, 9-, 12-months, and Follow-up visits
• Change in FVC, VC and MVV from baseline to the 4-weeks, 3-, 6-, 9-, 12-months, and Follow-up visits
• Change in CAFS from baseline to the 4-weeks, 3-, 6-, 9-, 12-months, and Follow-up visits
• Time from study inclusion and time of ALS symptoms onset to the use of definitive life supporting breathing assistance, or Death
Plasma concentrations of Apovir:
• Plasma concentrations Cpre dose of Apovir at the 4-weeks, 3-, 6-, and 12-months visits. Concentrations at 3 months will be compared to published data [Rhodes and Liu 2001 ; Khakoo et al 1998 ].
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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) | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
The randomisation will be stratified by presence/absence of treatment with Riluzole at baseline. |
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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 | 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 | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |