15-SG-0002 COL39_ICF Guide-V1

ICF GuideOverview Considerations Before Study Presentation • Prepare Your Team - Introduce the Study Team - Identify the PI or Sub-Investigator to Lead the Consenting Process • Establish LAR’s level of medical knowledge • Use Your Materials • Decide When to Introduce Study Educate LAR/Family About the Disease • Explain Seizures • Describe the progression to SRSE • Communicate Disease Severity • Explain SRSE Treatment Options • Establish expectation for Length of Stay in ICU/In Hospital Discuss Aspects of the Study • Talk About the Active Ingredient of SAGE-547 • Clarify Confusing Terms: - Standard of Care - Placebo - Randomization • Provide Detail About Adverse Events/Risks • Inform LAR about Retreatment Provide Information on Clinical Trials • FAQs

CONSIDERATIONS BEFORE PRESENTING THE STUDYPrepare Your Team Introduce the Study Team • If the study team is different than the attending physician/treating team, decide who from clinical team should introduce the study team (PI and Study Coordinator) to the LAR. This helps increase the family’s comfort level and ensure a smooth transition into the study discussion Identify the PI or Qualified Sub-Investigator to Lead the Consenting Process • Given the complex nature of SRSE and the STATUS Trial, consent discussions should be led by the PI or qualified sub-I • SC should be present to act as a resource for the family—they are a face of continuity throughout the study • If possible, include a member of the clinical team as well (physician or nurse). This will help convey the inter-disciplinary collaboration that is supporting the patient Establish LAR’s level of medical knowledge Understanding a LAR/patient’s background will help you provide the right amount of information for the LAR during consenting. There are five basic areas where the LAR may need education, including: – Clinical trials – Seizures – SRSE – STATUS Trial – ICU length of stay Based upon a LAR/patient’s experience, different topics might require more or less emphasis. For example, if a patient has a medical history of epilepsy, they may not require an education on seizures and the consent will likely go more quickly. A previously healthy SRSE patient may need to be educated about seizures as well as the study and will likely take longer to consent. AREAS OF EDUCATIONPatient Profile What is a clinical trial Seizure SRSE STATUS Trial ICU Length of Stay X XPre-Existing X X XEpilepsy X X XXChronic Disease X XXSRSE is anUnexpected Event

CONSIDERATIONS BEFORE PRESENTING THE STUDYUse Your MaterialsThe STATUS Trial has developed a number of materials to help support theconsenting process, including:• Consenting Tool (flip chart) — walks patients through the consenting process - If not local IRB approved, this can be used for study team education.• Disease Awareness Brochure — explains SRSE and its severity• Study Website (patient-facing) www.statustrial.com — to share information with extended family members. There are also downloadable patient resources here such as: - Disease Awareness Brochure - Trial Information Sheet - Physician Information Form (to pass along to their physician)EEGs: Several sites have used patients’ actual EEGs to demonstrate what seizureactivity looks like, what burst suppression looks like and what ‘normal’ EEGsshould look like. This can be a great visual tool to help the LAR understand what ishappening to their loved one“Decoding” the ICF: ICFs can be overwhelming documents. The PI can actas the “translator” for the ICF to make dense medical and legal jargon moreunderstandable for a family trying to understand the critical nature of the diseaseand its effects on their loved one. The PI can also be available to answer anyquestions or concerns following the review of the ICFDecide When to Introduce StudyInform SAGE of any potential patient, BEFORE you speak to the family/LAR• Triggers may include: - cEEG monitoring - Burst suppression - Administration of third-line agents• This step does not require you to attempt consent• Let SAGE know even if you want to treat the patient using your institution’s typical RSE/SRSE treatment plan before entering a patient into the study• Notifying SAGE about patients early and often allows them to have appropriate staff on hand to lend support as neededFor seizure naïve patients, consider waiting to present the study until after first weanfailure. Families who have never been through this:• May not be aware of the severity and lack of medical treatments available if done early in the process.• May be more receptive to a clinical trial if a patient fails the wean, once all other options have been tried

EDUCATE LAR/FAMILY ABOUT THE DISEASEExplain Seizures Define seizure: A seizure is a sudden surge of electrical activity in the brain like an electrical storm. Symptoms of seizures may be different each time and in each person, and most seizures do not last longer than 2 minutes Use the “headache analogy” Here’s a great analogy used by one PI: “Seizures are much like headaches. Both are symptoms caused by other things like trauma, tumors, infections or strokes. When we treat headaches, it is important to make the pain go away, but it is more important to understand what causes the headache and address this underlying disease. In this respect, we approach seizures in much the same way. The major difference is that headaches, while extremely uncomfortable, are not harmful. Seizures, on the other hand, are toxic to the human brain and have to be treated immediately.” Clear up misperceptions about seizures Many people associate seizures with shaking or convulsions. More often than not, a patient with refractory seizures may stop shaking physically, but the brain continues to undergo electrical seizures (which are considered just as toxic) and for this reason require EEG for monitoringDescribe the progression to SRSE When a seizure lasts too long or when they occur one after another so that the person cannot recover in-between, it is called status epilepticus (SE). SE is a life- threatening seizure condition that requires immediate medical attention. These patients are given anti-seizure medications in the Emergency Room Patients whose seizures continue despite the anti-seizure medication have refractory status epilepticus (RSE) and must be admitted to the intensive care unit (ICU) or neurocritical care unit (NCCU) to be placed in a medically induced coma using anesthesia. The anesthesia helps the seizures stop while doctors work to find the cause of the seizures and treat it. Doctors hope that by giving the brain a chance to rest it will “reset” itself and the brain cells will once again communicate normally The condition becomes super-refractory status epilepticus (SRSE) if patients continue to have seizures while doctors attempt to turn off the anesthesia

EDUCATE LAR/FAMILY1st/2nd Line Treatment ABOUT THE3rd Line Treatment DISEASE3rd Line Adjunct Treatment ~0–5 min ~5–30 min ~30 min–24 hrs ~24 hrsfrom start of seizure from start of seizure from start of seizure from start of seizure Seizure Status Refractory Super- Starts Epilepticus Status RefractoryHospital (SE) Epilepticus StatusDepartment: Epilepticus (RSE)Treatment: (SRSE) TRIAL CANDIDATE EmeErRgency Room ICU ICU/NCCU ICU ICU/NCCU • Seizure continues • 1st and 2nd line of • Seizure continues • Failure to wake from Aseniztuir-esmeeizdiucarteion • Medically induced coma to medically induced coma medications TRIAL CANDIDATE try Ato nlestsie-nsdeaimzaugreeto brain withoAunt ctoin-tsineuiozuus rseeizures medications medications TMReIAdiLcaClAlyNinDdIDucAeTdE CToRnIAtinLuCeAtNo DoIpDtAimTEize coma to minimize brain treatment approach damage Continue to treat underlying conditionCommunicate Disease Severity • These are usually some of the “sickest patients in the hospital” • The severity of the seizures is largely determined by how easily physicians can treat them and how many medications fail to control the seizures • Coma is not a natural body state and is extremely dangerous. It makes people prone to medical complications such as infections, clots, skin breakdown and malnutrition • Explain problems associated with repeated unsuccessful wean attempts - Brain damage can occur within an hour of continuous seizures - As many as half (30–50%) of SRSE patients may die and those who do survive have a high likelihood of significant physical and/or mental impairment - Time is critical to ensure the best outcomeExplain SRSE Treatment Options • The clinical team is trying all treatments available for this condition • Many people will be caring for your loved one including physicians, nurses, nutritionists, occupational and physical therapists, nurse and physician assistants and others • However, there are not many options for SRSE. The family may consider: - “Staying the course” and continue burst suppression/wean cycles. However, this has inherent risks - Trying something different, in the form of a clinical trial - Discussing comfort/withdrawal of care

EDUCATE LAR/FAMILY ABOUT THE DISEASEEstablish Expectation for Lengthof Stay in ICU/In Hospital • Emphasize that a patient with SRSE will usually remain in the hospital for several weeks or months • Participation in the STATUS Trial will not impact the length of a patient’s hospital stay • During their stay in the ICU, patients will experience complications and setbacks. The nurses and doctors can help families focus on the big picture and overall trajectory of care rather than minute to minute changes DISCUSS ASPECTS OF THE STUDYTalk About the ActiveIngredient of SAGE-547 • Study medication contains allopregnanolone which is an endogenous neuroactive steroid, meaning that it is a hormone that occurs naturally in the body • Study medication dosing levels during the blinded infusion are similar to the levels of the hormone found in the body during a woman’s 3rd trimester of pregnancyClarify Confusing Terms “Standard of Care” (SOC)—Avoid using the term with HCPs and families For HCPs: SOC implies that there are published guidelines; in physicians’ minds, there is no SOC but rather their institution’s guidelines to treat and many physcians’ approaches to managing SRSE patients is largely empirical since proven standards for treating these patients do not exist For families: SOC isn’t a term that resonates with them

DISCUSS ASPECTS OF THE STUDYClarify Confusing TermsExplain “placebo” Since all patients will receive treatment, consider re-defining placebo when speaking to families and LAR: Placebo arm SAGE-547 armAlternate description “We are doing everything we “We are doing everything we can to treat your loved one.” can to treat your loved one PLUS the study medication.”Regardless of which treatment arm they are assigned to, their medical team will: • Continue to treat their loved one and address problems as they come up • Do their best to provide the safest and best choices availableDescribe How Randomization Works Consider explaining randomization as a “coin toss”; there is a 50/50 chance your loved one will receive the investigational medication • This removes the perception that the study doctor/team is deciding which arm of the study to place the patient intoProvide Detail About Adverse Events/Risks • Emphasize that many patients from the Phase 2 Study had been in the ICU for greater than 6 weeks • SAEs were assessed to be the result of the underlying conditions that caused SRSE, or an extended stay in the ICU, and not due to study drug • Side effects of the dosage of study medication used in the STATUS Trial include: sleepiness and sedation in generally healthy patients (tremor, post-partum depression)Inform LAR about Retreatment Explain to the LAR that if the patient enrolls in the study and is unable to wean successfully without the seizures returning, they may have the opportunity to receive the study drug Avoid using the phrase “guaranteed” study drug • No patient is guaranteed retreatment • However, if a patient qualifies for retreatment then they will receive SAGE-547 • In order to qualify for retreatment: - The patient must complete the 6-day blinded infusion - At the end of the initial infusion, the study team will reassess to determine if the patient may benefit from and be eligible for the retreatment arm

PROVIDE INFORMATION ON CLINICAL TRIALSFAQsWhat is a clinical trial?A clinical trial evaluates the safety and effectiveness of an investigational drug. Aclinical trial can provide information on whether the investigational drug is betterthan, as good as, or no better than the standard treatment or placebo. Qualifieddoctors, nurses and other medical professionals conduct the trial. It is only throughthe completion of clinical research studies that the investigational drug can beevaluated, and if proven safe and effective, the drug is approved for general use.Clinical trials are performed according to government regulations that help protectthe safety and rights of the participants.What is an investigational drug?An investigational drug is a study medication that is not approved for use orprescription by doctors for the condition being studied. Investigational drugs aretested during clinical trials to see if they are safe and effective for a specific medicalcondition and/or group of people.Is participation in a clinical trial voluntary?Participation in any clinical trial is completely voluntary. If you decide to participatein a clinical trial, you are always free to withdraw at any time for any reason withoutany penalty or effect on your future medical care.What are the risks of participating in a clinical trial?Your friend, family or loved one could experience side effects associated withthe investigational drug. There are also risks associated with some of the studyprocedures. The symptoms may not improve or may get worse during the trial. Thedoctor or trial staff will discuss all of the possible risks and potential benefits indetail with you.What is informed consent?Informed consent is the process of learning the key facts about a clinical trialbefore you decide to participate. It is also a continuing process throughout thestudy to provide information to participants. To help you decide whether or notto participate, the doctors and nurses involved in the clinical trial will explain thedetails of the study. The study team will then provide you with an informed consentform to read. The document includes details about the study, such as its purpose,duration and required procedures. Risks and potential benefits are also explainedin the informed consent form. After you have received and read the informationabout the clinical research study, you will then decide whether or not to sign thedocument. No study-related procedures can take place before you have signed theinformed consent form. The informed consent form is not a contract, and you maywithdraw from the clinical trial at any time.

PROVIDE INFORMATION ON CLINICAL TRIALSFAQsIs my loved one’s personal information kept private?The information you provide will not be shared with anyone who is not directlyassociated with this trial without your permission (except as required by law).Why is my loved one in SRSE if they don’t have epilepsy?Epilepsy is a neurological condition where a person has had at least two seizuresthat were not caused by a medical condition. Most seizures in this instance usuallystop on their own or after seizure medications are administered. However, whena seizure is continuous and lasts for a prolonged duration, even after many typesof seizure medications are given, the patient may have super-refractory statusepilepticus (SRSE). Symptoms of SRSE may sometimes be related to commonforms of epilepsy, but a patient does not have to have epilepsy in order toexperience SRSE.iNeligan A, Shorvon SD. Epilepsy Res. 2011;93(1):1–10.iiBronen RA. Am J Neuroradiol. 2000;21(10):1782–1783.iiiShorvon S, Ferlisi M. Brain. 2011;134:2802–2818.