E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis (ALS) |
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E.1.1.1 | Medical condition in easily understood language |
ALS/ Motor Neuron Disease (MND) |
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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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine if Triumeq improves survival in patients with ALS |
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E.2.2 | Secondary objectives of the trial |
To determine if Triumeq improves secondary outcomes and selected biomarkers compared with placebo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years at the time of screening 2. Diagnosis of ALS according to the Gold Coast Criteria (Please see Table 1 of Shefner et al Clinical Neurophysiology 2020, also available in Appendix 2) 3. Capable of providing informed consent and complying with trial procedures 4. TRICALS risk profile > -6.0 and < -2.0 (See Section 4.3.4) 5. Those taking Riluzole must be on a stable dose for at least 30 days prior to the baseline visit or must have stopped taking Riluzole at least 30 days prior to the baseline visit 6. Women must not become pregnant (e.g., post-menopausal, surgically sterile, using highly effective birth control methods or not having potentially reproductive sex) for the duration of the study plus five days. Highly effective methods of birth control are those with a failure rate of < 1% per year when employed consistently and correctly, e.g. Combined (oestrogen and progestogen containing) hormonal contraception or progestogen-only hormonal contraception. For more information, please refer to the HMA CTFG Guidelines: https://www.hma.eu/fileadmin/dateien/Human_Medicines/01- About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf?fbclid=IwAR3AY5Ha0ESDyqIBeUaYI9VTFWmx9bbt8NZ-80N-5ME6pkBb1UHvFsTwqlQ 7. Women of childbearing potential must have a negative serum pregnancy test at screening and be non-lactating. Patients will be advised regarding appropriate contraception. A menstruation history will be taken at each visit. Women of childbearing potential are defined as females who are fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy (https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf?fbclid=IwAR3AY5Ha0ESDyqIBeUaYI9VTFWmx9bbt8NZ-80N-5ME6pkBb1UHvFsTwqlQ). 8. For participants taking antacids (regularly or as required), participant is willing and able to avoid taking antacids for at least 6 hours before and 2 hours after Triumeq 9. Participant taking taurursodiol supplements (TUDCA) can participate in this trial if the supplement does not contain sodium phenylbutyrate. 10. Participants taking taurursodiol supplements (TUDCA) that also contain sodium phenylbutyrate must be willing to stop supplementaiton 30 days prior randomisation. |
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E.4 | Principal exclusion criteria |
1. People who are HLA-B*5701 positive 2. Known hypersensitivity to Dolutegravir, Abacavir or Lamivudine, or to any of the excipients 3. Safety Laboratory Criteria at screening: ALT ≥ 5 times upper limit of normal (ULN) AST ≥ 3 times ULN Bilirubin ≥ 1.5 times ULN, with clinical indicators of liver disease Creatinine clearance < 30 mL / min Platelet concentration of < 100 x109 per L Absolute neutrophil count of < 1x109 per L Haemoglobin < 100 g/L Amylase ≥ 2 times ULN Lactate ≥ 2 times ULN 4. Moderate to severe hepatic impairment, as defined by local clinical guidelines 5. Presence of HIV antibodies at screening 6. Presence of Hepatitis C antibodies at screening unless participants have had effective treatment for Hepatitis C 7. Presence of Hepatitis B core or surface antigen at screening 8. Participation in any other investigational drug trial or using investigational drug within 30 days prior to screening 9. Use of NIV ≥22 h per day or having a tracheostomy 10. Edaravone dose within 30 days prior to screening. Edaravone is approved by the FDA and in Japan, but remains an investigational product in Europe and Australia 11. Clinically significant history of unstable or severe cardiac, oncological, psychiatric, hepatic, or renal disease or other medically significant illness 12. Taking medication contraindicated with Triumeq: Dofetilideor Fampridine (dalfampridine) 13. Taking Tofersen within 3 months prior to screening |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is overall survival, defined as time to mortality from any cause
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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) |
1. To assess the effect of Triumeq versus placebo on a combined assessment of survival and measures of daily functioning (CAFS) 2. To assess the effect of Triumeq versus placebo on measures of daily functioning 3. To assess the effect of Triumeq versus placebo on respiratory function 4. To assess the effect of Triumeq versus placebo on plasma creatinine 5. To assess the effect of Triumeq versus placebo on the time to reach advanced disease stages 6. To evaluate the safety of Triumeq administered orally to participants with ALS 7. To evaluate the tolerability of Triumeq administered orally to participants with ALS 8. To assess the effect of Triumeq versus placebo on change in cognitive functioning 9. To assess the effect of Triumeq versus placebo on change in quality of life 10. To collect research blood and urine samples for post-trial explanatory analyses; markers will be included e.g. urinary P75ECD, plasma neurofilament light and heavy chain, HERV-K, and genotyping
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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 | No |
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) | 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 | 11 |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |