Purpose of the ATLAS Study.

We’re conducting the ATLAS Study to assess the efficacy and safety of an investigational drug (tofersen*), as compared to placebo, to determine whether it may delay the onset of signs or symptoms of ALS and/or slow the decline in function once signs or symptoms appear in people who carry a confirmed SOD1 gene variant (that is associated with high/complete penetrance and a rapidly progressive disease) and do not have any clinical signs or symptoms that definitively indicate onset of ALS.

*Tofersen was approved by the FDA on April 25, 2023. Tofersen is an antisense oligonucleotide indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This indication is approved under accelerated approval based on reduction in plasma neurofilament light chain observed in patients treated with tofersen. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

A placebo is an inactive substance/intervention that looks the same as, and is given the same way as, the active drug being tested.

Who may qualify.

Eligible participants must:

  • Not have any clinical signs or symptoms that definitively indicate onset of ALS
  • Have a confirmed superoxide dismutase 1 (SOD1) gene variant that is associated with high/complete penetrance and rapidly progressive disease
    • Penetrance is the probability that individuals carrying a particular gene variant will actually develop the disease
  • Be 18 years of age or older

There are additional eligibility requirements that the study doctor will explain to you.

If you decide to take part in the study, all study-related treatments and assessments will be provided to you at no cost. Compensation for time and travel may be available. Participation is voluntary, and you will be able to leave the study at any point without penalty. We would just ask that you contact the study team, and they may ask you to visit the study center for one final visit with assessments.

What important medical question will this study ask?

The ATLAS Study is part of a larger clinical research effort to evaluate the safety, dosing, and efficacy of tofersen in people who have a confirmed SOD1 gene variant. This study will evaluate whether starting an investigational drug early (before clinical signs or symptoms that definitively indicate onset of ALS) will delay the appearance of signs or symptoms of ALS compared to placebo and/or reduce the loss of function over time as compared with starting the investigational drug once signs or symptoms appear.

Tofersen is designed to target the SOD1 gene and potentially reduce the level of SOD1 protein in people with ALS who carry a confirmed SOD1 gene variant.

What should I expect?

In order to enroll in the study, you will need to provide your informed consent to participate by signing the informed consent form (ICF), which details the study procedures and your responsibilities as a participant.

You will then need to attend the screening visit(s) for initial tests and assessments to see if you are eligible to participate. After all necessary tests and assessments have been completed, and if you are eligible to participate, you may choose to enter the study.

How long will study participation last?

The maximum study duration is approximately six years and six months.

Study participation.

What will happen during the study?

*Not everyone in Part A will move into Parts B, C, or D.

Screening period.

During this period, the study team will perform tests and procedures to make sure the study is a good match for you. To participate in this study, you must undergo genetic testing to see if you have one of the SOD1 gene variants included in this study. You will receive both pre-test and post-test genetic counseling sessions, and you may request additional genetic counseling as needed throughout the study at no cost. As a reminder, even if you have a SOD1 gene variant being studied, you may never develop any signs or symptoms of ALS.

This study has four segments: Parts A, B, C, and D. 

Part A.

If you test positive for one of the SOD1 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 length of Part A will vary.

What is neurofilament (NF)?

Neurofilament is a protein made by the body that is found in neurons. This study will use NF as a biomarker. Biomarkers are measurable substances in the body that can change as a result of disease or treatments. Examples of biomarkers include vital signs like pulse and blood pressure, changes detected on imaging tests, and laboratory tests like protein level measurements. Testing for biomarkers can sometimes help diagnose a certain disease, determine or predict the severity of the disease, or evaluate how well and safely a medicine may work in treating the disease.1,2

Individuals with one of the SOD1 variants being studied and with elevated NF levels may be more likely to develop signs or symptoms of ALS in the short term, but it is not certain they will. NF levels will be closely monitored as part of ATLAS Study participation. However, the exact NF level will not be disclosed to the participant or the study doctor.

Part B.

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 given intrathecally, which means that it is given to you by a procedure called a lumbar puncture. Before the investigational drug or placebo is given, a trained clinician will perform a lumbar puncture (LP). During the LP, the clinician will insert a needle into the fluid-filled space below the end of your spinal cord through your lower back. The clinician will take a sample of your cerebrospinal fluid and then inject the investigational drug or placebo.

A placebo is a substance that looks like the investigational drug but contains no active ingredients. Placebos help us make sure that any changes seen during the study are due to the investigational drug alone and not another reason. Participants are assigned their participant group at random (by chance), and neither they nor the study team is told which group they have been placed into until after the study is finished.

Part C.

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 definitively 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.

Part D.

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 definitively 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.

Can I leave the study if I change my mind?

Participation in any clinical trial is completely voluntary, and participants may choose to leave the study at any time for any reason. If you would like to leave the study, you should discuss this with your study doctor, who will give you information about how to do this safely.

Early termination/end of study visit.

If you stop the study early for any reason, you will have an end of study visit. This will occur about four weeks after the last dose of your assigned study treatment or four weeks after your last visit in Part A. An end of study visit will also be done if you complete treatment in Parts B, C, or D of the study. This visit may be completed at home or at the study center.

If you discontinue Part A, you will not be eligible to participate in Parts B, C, or D. Similarly, if you discontinue study treatment in Part B, you will not be eligible to participate in Part C.

 

How will participants’ health be monitored?

Because safety is our highest priority, you will have up to 34 visits at the study center and up to 58 home visits. These visits will take place approximately every 28 days (depending on which part and period of the study you are in), and the study team will conduct several assessments to monitor your condition.

Study assessments will vary from visit to visit, but may include:

  • Blood sample collection
  • Urine sample collection
  • Health questionnaires
  • Vital sign measurements (measurements of your temperature, heart rate, breathing rate, blood pressure, and weight)
  • Electrocardiogram (ECG; a test to check the electrical activity of the heart)
  • Lumbar puncture
  • Reporting signs or symptoms of ALS
  • Neurological exam
  • Physical exam

Some of these assessments may be uncomfortable or may carry certain risks; the study team will explain each assessment to you in detail if you decide to take part.

 

Are there any potential risks?

It’s important to remember that, as with any investigational drug, you can never be sure of the outcome. Your health may improve, it may stay the same, or it may get worse. This could happen even if you are assigned to the placebo group.

It's important that you tell the study team if you experience anything unusual during your time in the study.

Not all side effects of this investigational drug (tofersen) are known, and there may be side effects that are unpredictable.

  • In previous studies with the investigational drug, the most common side effects that occurred in participants who took tofersen were pain (including back pain or limb pain), feeling tired, muscle pain or stiffness, joint pain, nerve pain, and changes in cerebrospinal fluid tests (cerebrospinal fluid, or CSF, is the fluid that surrounds the brain and spinal cord).
  • Possible serious side effects seen in previous studies with tofersen include spinal cord inflammation, nerve root injury or irritation, swelling of the nerve inside the eye, and inflammation of the linings of the brain and spinal cord.
  • The effects of the investigational drug when combined with other medicines or substances, such as alcohol, are not fully known.
    • A combination of medicines and alcohol or other substances might result in serious or even life-threatening reactions.
    • Therefore, while you are in the study, you should always discuss the use of any medicine (over-the-counter, prescription, herbal, or supplement), or substances such as alcohol or recreational drugs, with your doctor.
  • We do not know the effects of tofersen on unborn babies.
    • Women who have not yet gone through menopause or are not surgically sterile (have had their ovaries and/or uterus removed) must be on effective birth control to enter and remain in Parts B, C, and D of this study.
  • Women who are breastfeeding cannot take part in Parts B, C, and D of this study because the effects of tofersen on breast milk and breastfeeding infants are unknown.

Further details regarding risks and potential side effects are provided to you in the informed consent form. Always talk to your study doctor about any concerns you have at any point during the study.

See if you may qualify

References.

  1. ALS Association (n.d.). Biomarkers. www.als.org/research/research-we-fund/scientific-focus-areas/biomarkers. Accessed 18 March, 2022.
  2. U.S. Food & Drug Administration (2017, March 3). What are biomarkers and why are they important? transcript. www.fda.gov/drugs/biomarker-qualification-program/what-are-biomarkers-and-why-are-they-important-transcript. Accessed 18 March, 2022.