<p>The University of Plymouth Faculty of Health is part of the TRICALS consortium</p>



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Professor of Neurology

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Oliver Hanemann - TRICALS

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<h3>Investigational drug</h3>
Approximately 2% of people living with ALS have a mutation in the <em>SOD1</em> gene. Mutations in the <em>SOD1</em> gene can lead to the production of abnormal SOD1 protein that is likely to be toxic to cells and could possibly lead to nerve cell death observed in people with ALS. The ATLAS study is evaluating whether an investigational drug (tofersen) may delay the onset of signs or symptoms of ALS and/or slow the decline in function once clinical signs or symptoms appear (compared to the initiation of tofersen at the time of, or after, emergence of ALS)

Tofersen (BIIB067) is an antisense oligonucleotide (ASO), which is designed to reduce levels of SOD1 protein in people with ALS associated with a <em>SOD1</em> gene variant.
<h3>Study overview</h3>
The study is comprised of 4 parts as described below.

<img class="alignnone wp-image-23821" src="https://backend.tricals.org/wp-content/uploads/2023/02/26802_Biogen_ATLAS-Study_Editable_Schematic_092722_EN.jpg" alt="" width="950" height="441" />
<h3>Part A</h3>
If you test positive for one of the <em>SOD1</em> gene variants being studied and pass other screening tests, you will be eligible to enter Part A of the study. During this part, you will not receive any study treatment, but your health status and neurofilament (NF) level will be closely monitored (at home or at the study center). The study team will evaluate your blood samples monthly for an NF level that is above the threshold. You and the study doctor will know when the NF level is above the threshold to consider eligibility for the next part of the study (Part B). The duration of Part A will vary.
<h3>Part B</h3>
If your NF level increases above the pre-determined threshold during your participation in Part A, the study doctor will evaluate the cause of the increase in NF. If the study doctor determines that the NF increase is not attributable to an alternative cause unrelated to ALS disease activity, you may choose to be screened for eligibility for potential participation in Part B. During this part of the study, you will be assigned to receive either the investigational drug or a placebo. You will be assigned randomly by a computer, and you will have an equal chance of receiving the investigational drug or placebo. Neither you nor the study team will know whether you received the placebo or the investigational drug; this is called a double-blind period.

The investigational drug or placebo is delivered intrathecally. Intrathecally means that the study drug is given to you by a procedure called a lumbar puncture.
<h3>Part C</h3>
If you show signs or symptoms of ALS during Part B of the study and your study doctor and a group of independent reviewers confirm that these signs or symptoms definitely indicate onset of ALS, you may choose to be screened for eligibility for potential participation in Part C of the study. During this part, everyone will receive the investigational drug; this is called an open-label period. The total length of participation in Parts B and C of the study is up to approximately two years.
<h3>Part D</h3>
If you start to show signs or symptoms of ALS during your participation in Part A or during screening for Part B, and your study doctor and a group of independent reviewers confirm that these signs or symptoms definitely indicate onset of ALS, you may choose to be screened for eligibility for potential participation in Part D of the study. Part D is another open-label period during which everyone will receive the investigational drug. The total length of participation in Part D is up to approximately two years.
<h3>Key Eligibility Criteria</h3>
To be able to enroll in the ATLAS study (Part A), participants need to:
<ul>
 	<li>Not have any signs or symptoms of ALS (that definitely indicate onset of ALS)</li>
 	<li>Have a certain <em>SOD1</em> mutation (that is associated with high/complete penetrance and rapid disease progression)</li>
 	<li>Be 18 years of age or older</li>
 	<li>Have a plasma NF level below the pre-defined threshold</li>
</ul>
If you are eligible and choose to participate, you will receive the following at no cost:
<ul>
 	<li>Comprehensive study-related health evaluations and assessments, including genetic testing</li>
 	<li>Investigational drug or placebo</li>
 	<li>All study-related visits and care</li>
</ul>
<h3>Travel Support</h3>
Assistance with travel and accommodations, and reimbursement for study-related expenses may also be available.

&nbsp;

ATLAS trial

Industry trial

<h3>ION363</h3>
The study drug (ION363) is designed to target the mutated FUS gene, which makes FUS protein. When FUS protein builds up in motor neurons, it may contribute to ALS. The study drug is designed to stop the FUS gene from making this protein, which may improve symptoms of ALS.
<h3>Study design</h3>
The FUSION trial is a phase 1-3 double-blind, randomized, placebo-controlled study. This means that the efficacy of ION363 is compared to a placebo. A placebo is a drug without an active ingredient. In Part 1 of the study, particpants will be randomly assigned to either the placebo or ION363. You will have a 2/3 chance of receiving ION363 in the first part of the study. Neither you nor your study doctor or the study staff will know which treatment you are receiving during that time. All participants will then have the opportunity to receive ION363 in Part 2 of the study.

You will receive the study drug or placebo as an injection through the spinal canal. The injection will take 1 to 3 minutes. You may receive local anesthesia to make the injection more comfortable.

The study consists of two parts. The total study duration is 3 years and 11 months. Part 1 of the study involves up to 2 weeks of a screening period, approximately 14 months for treatment (ION363 or placebo) and 3 months of post-treatment follow-up. During the treatment period, if your condition worsens significantly, you may be eligible to change early into Part 2 of the study where everyone receives ION363.

After completion of Part 1, you can continue to Part 2 which includes up to 20 months of treatment with ION363 followed by 9 months of post-treatment follow-up. After Part 2 of the study, you may continue to receive injections of ION363 for up to 3 additional years if the drug is not commercially available.

During the study there will be approximately 20 visits (9 visits for Part 1 and 11 visits for Part 2). The length of your visits will vary. One visit will require overnight stay and visits when the study drug is being administered will require at least 6 hours at the study site. You might have to stay overnight at the study site if your study doctor feels that it is best to observe you overnight for your safety.
<h3>Can I participate in the study?</h3>
The main criteria to participate in this study are:
<ul>
 	<li>You are at least 12 years old</li>
 	<li>You have ALS with a mutation in the FUS gene</li>
</ul>
<h3>Registration and more information</h3>
If you are interested in participating in the FUSION trial and fit the above profile, please contact one of the participating tricals centres below (contact details can be found by clicking on ‘read more’). They can provide you with more information and answer any questions you may have.

FUSION trial

<h2><strong>AMX0035</strong></h2>
AMX0035 consists of a combination of two molecules: tauroursodeoxycholic acid (TUDCA) and sodium phenylbutyrate. Both were previously shown to be safe and well tolerated. The combination of the two drugs is believed to decrease nerve cell damage in people living with ALS.
<h2><strong>Study overview</strong></h2>
This phase 3 study is a double-blind, randomized, placebo-controlled study. This means that we compare the effect of AMX0035 against the effect of a placebo. A placebo is a drug without an active ingredient, a 'fake drug'. The study drug and placebo are supplied in a sachet and must be dissolved in 1 cup of water. Either treatment should be taken orally (ingested) daily for 48 weeks. Participants will be randomly assigned to receive the placebo or AMX0035 treatment. The participant and the research team do not know which treatment the participant is receiving.

During a period of 1 year, participants will visit the research centre approximately 6 times for examinations. They will furthermore be contacted approximately 9 times by telephone or video calling.
<h2><strong>Key Eligibility Criteria</strong></h2>
The main criteria to participate in this study are:
<ul>
 	<li>You are diagnosed with ALS</li>
 	<li>The duration of illness from the first symptoms is no longer than 24 months</li>
 	<li>Your lung function is at least 55%, without using a ventilator</li>
 	<li>You must not be pregnant or breast-feeding for the entire duration of the study</li>
 	<li>If you have or are considering having diaphragm pacing during the study, you cannot participate</li>
 	<li>When using Riluzole: a stable dose of ≥30 days prior to participation</li>
</ul>
Participants can continue their treatment with Riluzole for the entire duration of the study.

Amylyx is looking to enrol 600 participants worldwide. Currently, the study is active in the following European countries: the United Kingdom, Ireland, the Netherlands, Spain, Sweden, Italy, France, Poland, Belgium, Germany and Portugal.
<h2><strong>More information</strong></h2>
More information about the PHOENIX trial can be found on the website of <a href="https://www.amylyxalstrial.com" target="_blank" rel="noopener">Amylyx</a> and <a href="https://clinicaltrials.gov/ct2/show/NCT05021536" target="_blank" rel="noopener noreferrer">here</a>.

Inclusion for this trial is closed.

PHOENIX trial

<h2><strong>FNP122</strong></h2>
Oxidative stress is thought to contribute to nerve cell death in ALS. FNP122 is an oral formulation of edaravone, a compound that can help prevent oxidative stress. Therefore, by decreasing oxidative stress, edaravone could potentially slow ALS progression.
<h2><strong>Study design</strong></h2>
The ADORE trial is <a href="https://www.ferrer.com/en/node/3250">sponsored</a> by the pharmaceutical company Ferrer. It is a randomised, double-blind, placebo-controlled trial. This means that the effect of FNP122 is compared against a placebo treatment. A placebo is something that looks exactly the same as the study medicine but does not have any active medicine in it. Participants will be randomly assigned to receive FNP122 or placebo. Neither the participant nor the study team will be told which group they have been placed into until after the study has finished.

Both placebo and FNP122 need to be dissolved in water and ingested daily. The study will run for up to 48 weeks. Participants will need to visit the clinic at various occasions:
<ul>
 	<li>For a screening appointment</li>
 	<li>For a baseline visit</li>
 	<li>At week 4</li>
 	<li>At week 12</li>
 	<li>Every 12 weeks thereafter</li>
</ul>
Monthly telephone appointments will take place in between the visits to the clinic until Week 48.
<h2><strong>Inclusion criteria</strong></h2>
Key eligibility criteria for people with ALS to participate, include:
<ul>
 	<li>Age between 18 – 80 years</li>
 	<li>Diagnosis of ALS</li>
 	<li>Disease onset within the prior 24 months</li>
 	<li>SVC equal to or more than 70% at screening visit</li>
 	<li>Change in ALSFRS-R score between 0.35 points and 1.5 points per month (both inclusive) in the period from onset of first symptoms to the Screening visit;</li>
 	<li>Patients on riluzole should be on stable doses ≥30 days prior to the baseline visit and this dose should be maintained during the entire trial.</li>
 	<li>Female participants should not be (able to become) pregnant or breast-feeding</li>
</ul>
Participants can continue their treatment with Riluzole for the entire duration of the study.

The study aims to enrol 300 patients across European countries. Several TRICALS Centres will be <a href="https://www.tricals.org/en/news/adore-trial-enrolls-first-patient/">participating</a> in this trial. Currently, the study is active in the United Kingdom, Ireland, the Netherlands, Belgium, Poland, Italy, Germany, Spain, France and Sweden.

Inclusion for this trial is closed.

ADORE trial

<h3><strong>Reldesemtiv in people with ALS</strong></h3>
Reldesemtiv was developed by Cytokinetics in order to counteract the decline in muscle function. In a phase 2 study, the drug was tested in people with ALS for a 12 week period. The current study is testing its effectiveness in the longer term and in a larger group of people.
<h3><strong>Study design</strong></h3>
This phase 3 study is a double-blind, randomised, placebo-controlled study. This means we are comparing the effects of reldesemtiv against the effects of a placebo. A placebo is a drug without an active ingredient, a ‘fake drug’.

Both reldesemtiv and the placebo should be taken as a daily capsule. Participants will be randomly allocated either the placebo or reldesemtiv. Neither the participant nor the research team will know whether the participant is receiving the placebo or reldesemtiv.

The entire study will last 48 weeks. Participants will be examined in hospital 8 times during this period. Participants will receive either reldesemtiv or a placebo during the first 24 weeks.  All participants will receive reldesemtiv during the second 24 weeks.
<h3><strong>Entry criteria</strong></h3>
The main entry criteria for participating in this study are as follows:
<ul>
 	<li>Participants must be between 18 and 80 years old</li>
 	<li>Disease onset within the last 24 months</li>
 	<li>The participant's lung function is at least 65%, without the use of a ventilator</li>
 	<li>When using Riluzole: a stable dose of ≥30 days prior to participation</li>
 	<li>Participants are not pregnant or breastfeeding</li>
 	<li>Participants haven’t participated in another clinical trial in the past 30 days</li>
</ul>
<em>Note: This list is not exhaustive, but these are the main criteria.</em>

Participants can continue their treatment with Riluzole for the entire study duration. Participants can also participate in the study if they don’t take Riluzole.

COURAGE-ALS Trial

<h3>Pegcetacoplan</h3>
Pegcetacoplan (also known as APL-2) has not previously been tested in people with ALS, but has been tested in previous trials in healthy volunteers and people with blood, kidney and eye diseases. Researchers believe that the immune system is changed in people with ALS and that this contributes to nerve cell loss. Pegcetacoplan is designed to shut down the functioning of part of your immune system. Therefore, it is now being investigated whether pegcetacoplan can possibly prevent the loss of nerve cells.
<h3>Study design</h3>
This phase 2 study was commissioned by Apellis Pharmaceuticals and is a double-blind, randomised, placebo-controlled study. This means we’re comparing the effects of pegcetacoplan with the effects of a placebo. A placebo is a drug without an active ingredient, a ‘fake drug’.

Both pegcetacoplan and the placebo are to be administered by injection twice a week. Participants are randomly assigned either the placebo treatment or the pegcetacoplan treatment. Neither the participant nor the research team will know which treatment the participant receives.

The entire study will last 116 weeks, which is approximately 2 years. During this period, the participant will visit the hospital 11 times for examinations. Participants will receive treatment with pegcetacoplan or the placebo for 52 weeks. After this phase, all participants will enter the 'open label' phase, during which everyone will receive pegcetacoplan.
<h3>Entry criteria</h3>
The main criteria for participation in this study are as follows:
<ul>
 	<li>The participant is at least 18 years old</li>
 	<li>The duration of their illness is no more than 72 weeks from when symptoms first appeared</li>
 	<li>The participant's lung function is at least 60%, without the use of a ventilator</li>
 	<li>Participants must not get pregnant or be breastfeeding throughout the duration of the study</li>
 	<li>Participants have been vaccinated within the last 5 years, or are willing to be vaccinated, against pneumococcus (<em>Streptococcus pneumoniae</em>), meningococcus (<em>Neisseria meningitidis</em>; types A, C, W, Y and B), and HiB (<em>Haemophilus influenzae</em> type B).</li>
 	<li>If the participant has a diaphragm pacing or considers undertaking the procedure during the study, participation is not possible</li>
 	<li>When using Riluzole: a stable dose of ≥30 days prior to participation</li>
 	<li>When using Edaravone: a stable dose of ≥60 days prior to participation</li>
</ul>
This study requires 228 participants from different countries. Several TRICALS centres are participating in this study. The study is currently ongoing in the following European countries: The Netherlands, Belgium, France, Ireland, Italy, and Spain.

APL2-ALS-206 Trial

TUDCA (tauroursodeoxycholic acid) is a small molecule that is being explored for its potential as a treatment for amyotrophic lateral sclerosis (ALS). TUDCA may decrease nerve cell death through its ability to act as an antioxidant that prevents toxic reactive oxygen from accumulating inside cells. There may also be an effect on immune function.
<h3>Study setup</h3>
TUDCA-ALS is a randomized, double-blind, placebo-controlled study. This means the effect of TUDCA is tested by comparing a group of patients that receive TUDCA to a group of patients receiving a placebo-drug. Patients will be randomized to one of two treatment arms. During the study, both the patient as the research team do not know who is receiving placebo or TUDCA. This will help researchers to assess potential side- and treatment effects of TUDCA.

TUDCA and the placebo capsules are ingested twice daily, 10-15 minutes after a meal. Patients will also be taking riluzole. The study duration is 18 months and clinical assessments during the trial phase will be performed every three months. This will allow measuring if the drug improves disease progression rate.
<h3><b>Would you like to participate?</b></h3>
Key eligibility criteria for people with ALS to participate, include:
<ul>
 	<li>Between 18 and 80 years old</li>
 	<li>Diagnosed with ALS</li>
 	<li>Disease duration ≤ 18 months</li>
 	<li>No swallowing difficulty</li>
 	<li>Forced vital capacity ≥70% of predicted values</li>
 	<li>On a stable dose of riluzole for at least 3 months</li>
</ul>

University of Plymouth

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