Common use of During the Study Clause in Contracts

During the Study. The events below will take place throughout the study. If you would like to know when exactly these will take place, please ask the study staff. • You will be asked about any updates to your medical history. This includes medication, drug, alcohol, and tobacco use • Physical exams, including skin exam o Photographs of the skin may be taken if the study clinician thinks it is needed. Photographs are photographic images of the skin that the study team may take of you during the study. You will not be identified in these photographs. However, if you have any markings on the area of your skin photographed, like a tattoo, those markings may appear in the photographs. Pfizer will own these photographs. The photographs will be used and shared along with your study records, as described in this consent document. In addition, the photographs may be used in publications, presentations, brochures, or other ways. The photographs may be used along with text, graphics, or audio materials. You will not be identified by name in any use of the photographs. By signing this consent document, you are giving permission for the study staff to take these types of photographic images and for the uses described above. • The use of proper birth control will be confirmed/reviewed (males only) • Xxxxx xxxxx. Your oral temperature may also be measured • Weight will be measured (Part B only) • ECGs will be collected o It may be necessary to shave or trim hair on your chest so that the patches for the ECGs will stick to your skin o Your chest may be marked with a pen to identify the correct areas for ECG patch placement • Continuous heart monitoring will be done for at least 8 hours after each dose (Part A only, except for Japanese dosing group, if done). There will also be a period of at least 2 hours (Day -1, Period 1 only) where monitoring will be done before the first dose o This involves the attachment of a small box like unit (transmitter) to your chest o The box is attached by a few wires (similar to those of an ECG) o The monitor sends information about your heart’s activity by a radio signal to a monitor o You may not sleep during the 2 hours of continuous monitoring done before dosing o You will need to stay in the procedure room for at least 4 hours after dosing while attached to the monitor o You will need to keep the box with you during the monitoring period o You will be asked to minimize activity while attached to the monitor • You will be asked: “How do you feel?” each day • An intravenous (IV) catheter may be placed in a vein in one of your arms for blood collection • OGTTs will be done (Part A [non-Japanese participants only] and B only) • The study investigator may decide to do an alcohol breath test at any time • You may be tested for COVID-19 • Blood and urine samples will be collected at various times throughout the study o Safety Labs: The blood and urine samples will be used for safety labs including the following: ▪ Urine samples to test for drugs of abuse ▪ Blood tests for Fibrinogen ▪ Blood tests for PT/INR/aPTT ▪ Blood tests for lipid panel, amylase, lipase, TSH, and free T4 (Part B only) o Any leftover urine, serum or plasma (components of blood) taken during the study may be stored and used to assess exploratory safety biomarkers or unexpected safety findings or for other exploratory purposes, including genetic analysis ▪ Biomarkers are natural substances in your body that can be used to show how your body works ▪ Samples to be used for this purpose will be kept for up to 1 year following completion of this study o Study Drug Levels: Blood and urine (Part B only) samples will be used to measure the levels of study drug and midazolam (Part C only). Blood samples from Part B will also be used for metabolite profiling. The samples will also be used to evaluate safety aspects related to any concerns during or after the study ▪ As part of understanding how your body absorbs, distributes, and gets rid of the study drug, the samples may also be used for the following: ⮚ Metabolite identification ⮚ Check the laboratory test which measures the study drug ⮚ Other internal exploratory purposes o Biomarkers: Blood samples will also be used to measure biomarkers ▪ Cholesterol (part B and C only) ▪ 4β-hydroxycholesterol (part B and C only) ▪ CP-I (Part B only) ▪ OGTT biomarkers (Part A [non-Japanese participants] and B only) ⮚ Plasma glucose ⮚ Serum insulin and C-peptide ⮚ GLP-1, GIP, Glucagon (Part B only) Biomarker samples may also be used to: ▪ Evaluate safety or efficacy (ability to produce a desired or intended effect) aspects related to any concerns arising during or after the study ▪ Check the laboratory tests which measure the biomarkers ▪ Other internal exploratory purposes o Retained Research Samples: Samples of your blood will be collected, stored, and used to learn more about the study drug ▪ Biological substances in your samples, including your genes and biomarkers, may be studied ▪ These samples may be kept by Pfizer for as long as the samples are useful for scientific research. This may be for many years (no time limit) • You will return to the CRU for a follow-up visit about 7 days after the last dose • You will receive a follow-up phone call about 4 weeks after the last dose • For safety reasons we may add procedures at any time during the study to check on your health status Blood Draws Blood samples will be taken by individual needlesticks, or by a catheter. A catheter is a small tube that is placed in a vein in your arm to take blood when required. Catheters are used when ordered by the study investigator or when required by the study plan. They are not used at the request of the participant. Part A There will be about 60 blood draws for dosing groups 1, 2, and 4, and 23 for dosing group 3 during the study. The total amount of blood drawn during the study for dosing groups 1, 2, and 4 is about 545 mL. This is equal to about a little more than 18½ oz or about a little more than 2¼ cups. The total amount blood drawn during the study for dosing group 3 is about 190 mL. This is equal to about a little more than 6¼ oz or about a little more than ¾ of a cup. Part B There will be about 46 blood draws during the study. The total amount of blood drawn during the study will be about 540 mL. This is equal to about a little more than 18¼ oz or about a little more than 2¼ cups Part C There will be about 34 blood draws during the study. The total amount of blood drawn during the study will be about 200 mL. This is equal to about a little more than 6¾ oz about a little more than ¾ of a cup. For comparison, the standard blood donation is about 16 oz. (2 cups), once in any 56-day period. As with all studies with blood draws, rest, hydration, and good eating habits are recommended. Blood loss in this amount (Part A, dosing groups 1, 2 and 4, and Part B only) may lead to a low red blood cell count (anemia). Anemia can make you feel more tired than usual. Possible Risks and Discomforts Taking part in this study has some risks. The study drug or procedure(s) may make you feel unwell or uncomfortable or could harm you. If you do not understand what any of the side effects described below mean, please let us know. The study investigator or study staff will explain them to you. It is important that you report all side effects that you have as soon as they occur. This is regardless of whether or not you believe they are caused by the study drug or your participation in this study. If you are not honest about any side effects that you have during the study, you may be harmed by staying in the study. Study Drug Risks During this study, you may receive either placebo and/or the study drug. The study drug is not expected to cause significant safety issues at the dose levels planned in this study. You may experience risks or discomforts when taking part in this study, and a summary of potential risks and discomforts will be provided to you (see below). You may also experience risks or discomforts that are unknown at this time. The study drug has been given to rats and monkeys for up to 2 weeks. While animal studies do not always predict the side effects that people may experience, the data that has been collected on the study drug to date are summarized here. All noteworthy findings in these animal studies were seen at much higher blood concentrations of study drug than may be tested in this clinical study. The study staff will be carefully monitoring your health and watching for these types of events. There were no noteworthy effects in the 2-week study in rats. In the 2-week study in monkeys, at a dose level that is similar to the highest dose that you may receive in this clinical study, some of the animals experienced the following: • Ate less food and lost weight • Vomited occasionally • Had soft feces These did not affect the health of the monkeys. There were changes in blood and chemical laboratory tests. These were not considered to be serious as the changes were small, and because there were no negative clinical effects. At the highest dose in monkeys, which was about 2 times higher than the maximum possible dose that anyone may receive in this study, the animals lost a greater amount of weight. At this high dose, the following were also seen: • Larger changes in blood and chemical laboratory tests • Some changes in the liver and kidney were seen under a microscope • This was not seen in all animals in this dose group This means that, at the highest dose, there was some injury to parts of the kidney, and corresponding decreases in kidney function were seen in the blood tests. There was also injury to some parts of the liver, and corresponding changes in liver function blood tests were seen. The study investigator will be monitoring your blood and urine samples and carefully monitoring your health throughout the study. Across all dose levels in monkeys, a few animals had minor red or pink discoloration of their skin after about 11 days of daily oral dosing with the study drug that was not considered serious. In a study focused on cardiovascular safety (heart health), where monkeys received study drug, there were no changes in heart rate or blood pressure, even at high doses. There were small changes in an ECG measurement (called QTc), but these changes were not considered serious. At the starting dose for this clinical study, the level of study drug in your blood is expected to be at least 285 times lower than the dose tested in monkeys where no significant negative effects were seen. At the maximum dose that may be tested in this study, the level of study drug in your blood will not be expected to be higher than at the dose tested in monkeys where no significant negative effects were seen. There is a possible risk of skin irritation from UV light exposure when taking the study drug. This has not been evaluated in animals. You will be asked to take precautions including avoiding tanning and prolonged sun exposure and should wear sunscreen. Midazolam Risks The most common side effects of midazolam liquid include: • Nausea • Vomiting • Dizziness • Drowsiness Midazolam may cause serious side effects including: • Hives • Difficulty breathing • Swelling of the face, lips, tongue, or throat • Severe dizziness • Mood changes • Agitation • Aggressive behavior • Uncontrollable movements • Shaking or tremor • Slow or fast heartbeat • Vision changes • Blurred vision • Fainting • Itching • Rash • Rapid, slow, or shallow breathing When you take more than one drug at a time, side effects can be more or different than if you take either drug by itself Until you know how the study drugs will affect you, you should use caution by: • Avoiding stairs • Not driving a car • Not swimming or bathing in a tub • Not working with machinery or at heights Other Risks Because the study drug is investigational, all of its side effects are not known. There may be rare and unknown side effects. These include reactions that may be life-threatening. All drugs have a potential risk of an allergic reaction. If an allergic reaction is not treated quickly, it could become life-threatening. You should get medical help right away (by calling 911 or immediately going to an emergency room) if you think you have any of the following symptoms: • Trouble breathing • Wheezing • Difficulty swallowing • Swelling of the face, mouth, lips, gums, tongue, or neck Other allergic reactions may include: • Itchiness • Rash • Hives • Blisters • Palpitations (racing heart) • Chest discomfort/tightness • Muscle pains/stiffness At times, the following may also be symptoms of an allergic reaction: • Diarrhea • Nausea • Vomiting • Abdominal pain If a significant side effect occurs, the following may be done: • Tests or treatment may be given as needed for your safety • Depending on how severe your symptoms are, you may be seen by outside medical providers or a hospital. This would be for further evaluation and/or treatment • The study investigator may notify your emergency contact as appropriate in the event of an emergency while you are taking part in the study Additional Risks or Discomforts Testing of DNA and/or RNA (deoxyribonucleic acid and/or ribonucleic acid) Genes are pieces of DNA that give coded instructions for the body. Parts of the code are passed down from parents to their children. The genes in your samples may be studied. This may include analyzing all of your genetic information. This is called “whole genome sequencing.” While collection of genetic information does not expose you to physical risk, collection of such information may result in a loss of your privacy if your genetic information is lost or stolen. There is a very small chance that your genetic information could be misused by people not involved with the research, including to discriminate against you. However, steps are in place to prevent a particular result from being linked to you and to prevent unauthorized people from even knowing genetic research was done. U.S. federal law prohibits discrimination in health insurance coverage and employment based on a person’s genetic data. However, U.S. federal law does not protect against discrimination when you are applying for: • Life insurance • Long term care insurance • Disability insurance You should talk to your physician or genetic counselor about the potential for genetic discrimination. The results of tests on your sample(s) will not be given to: • You • The study investigator • Any insurance company • Your employer • Your family • Any physician who treats you Blood Samples and IV Catheters (if used) Possible side effects of having your blood drawn or an IV catheter inserted include: • Bleeding at the site of the needle puncture • Bruising • Feeling faint • Rarely, infection or blood clot • Redness of the vein • Inflammation of the vein • Swelling • Pain • Nerve damage • Vein irritation from the fluid or medication being given • Local swelling due to IV fluid accidentally entering the tissue rather than the vein • Scarring If you feel faint, tell one of the study staff immediately.

During the Study. The events below will take place throughout the study. If you would like to know when exactly these will take place, please ask the study staff. • You will be asked about any updates to your medical history. This includes medication, drug, alcohol, and tobacco use • Physical exams, including skin exam o Photographs of the skin may be taken if the study clinician thinks it is needed. Photographs are photographic images of the skin that the study team may take of you during the study. You will not be identified in these photographs. However, if you have any markings on the area of your skin photographed, like a tattoo, those markings may appear in the photographs. Pfizer will own these photographs. The photographs will be used and shared along with your study records, as described in this consent document. In addition, the photographs may be used in publications, presentations, brochures, or other ways. The photographs may be used along with text, graphics, or audio materials. You will not be identified by name in any use of the photographs. By signing this consent document, you are giving permission for the study staff to take these types of photographic images and for the uses described above. • The use of proper birth control will be confirmed/reviewed (males only) • Xxxxx xxxxx. Your oral temperature may also be measured • Weight will be measured (Part B only) • ECGs will be collected o It may be necessary to shave or trim hair on your chest so that the patches for the ECGs will stick to your skin o Your chest may be marked with a pen to identify the correct areas for ECG patch placement • Continuous heart monitoring will be done for at least 8 hours after each dose (Part A only, except for Japanese dosing group, if done). There will also be a period of at least 2 hours (Day -1, Period 1 only) where monitoring will be done before the first dose o This involves the attachment of a small box like unit (transmitter) to your chest o The box is attached by a few wires (similar to those of an ECG) o The monitor sends information about your heart’s activity by a radio signal to a monitor o You may not sleep during the 2 hours of continuous monitoring done before dosing o You will need to stay in the procedure room for at least 4 hours after dosing while attached to the monitor o You will need to keep the box with you during the monitoring period o You will be asked to minimize activity while attached to the monitor • You will be asked: “How do you feel?” each day • An intravenous (IV) catheter may be placed in a vein in one of your arms for blood collection • OGTTs will be done (Part A [non-Japanese participants only] and B only) • The study investigator may decide to do an alcohol breath test at any time • You may be tested for COVID-19 • Blood and urine samples will be collected at various times throughout the study o Safety Labs: The blood and urine samples will be used for safety labs including the following: ▪ Urine samples to test for drugs of abuse ▪ Blood tests for Fibrinogen ▪ Blood tests for PT/INR/aPTT ▪ Blood tests for lipid panel, amylase, lipase, TSH, and free T4 (Part B only) ▪ Blood tests for HbA1c o Any leftover urine, serum or plasma (components of blood) taken during the study may be stored and used to assess exploratory safety biomarkers or unexpected safety findings or for other exploratory purposes, including genetic analysis ▪ Biomarkers are natural substances in your body that can be used to show how your body works ▪ Samples to be used for this purpose will be kept for up to 1 year following completion of this study o Study Drug Levels: Blood and urine (Part B only) samples will also be used to measure the levels of study drug and midazolam (Part C only). Blood samples from Part B will also be used for metabolite profiling. The samples will also be used to evaluate safety aspects related to any concerns during or after the study Saxenda ▪ As part of understanding how your body absorbs, distributes, and gets rid of the study drug, the samples may also be used for the following: ⮚ Metabolite identification ⮚ Evaluate safety aspects related to any concerns during or after the study ⮚ Check the laboratory test which measures the study drug ⮚ Other internal exploratory purposes o Biomarkers: Blood samples will also be used to measure biomarkers ▪ Cholesterol (part B and C only) ▪ 4β-hydroxycholesterol (part B and C only) ▪ CP-I (Part B only) ▪ OGTT biomarkers (Part A [non-Japanese participants] and B only) ⮚ Plasma glucose ⮚ Serum insulin and C-peptide ⮚ Plasma GLP-1, GIP, Glucagon (Part B only) Biomarker samples may also be used to: ▪ Evaluate safety or efficacy (ability to produce a desired or intended effect) aspects related to any concerns arising during or after the study ▪ Check the laboratory tests which measure the biomarkers ▪ Other internal exploratory purposes o Retained Research Samples: Samples of your blood will be collected, stored, and used to learn more about the study drug ▪ Biological substances in your samples, including your genes and biomarkers, may be studied ▪ These samples may be kept by Pfizer for as long as the samples are useful for scientific research. This may be for many years (no time limit) • You will complete C-SSRS and PHQ-9 questionnaires • You will return to the CRU weekly while dosing with Saxenda at home • Your dosing diary will be reviewed for dosing compliance • Your Saxenda injection sites will be checked • You will return to the CRU for a follow-up visit about 7 days after the last dose • You will receive a follow-up phone call about 4 weeks after the last dose • For safety reasons we may add procedures at any time during the study to check on your health status Blood Draws Blood samples will be taken by individual needlesticks, or by a catheter. A catheter is a small tube that is placed in a vein in your arm to take blood when required. Catheters are used when ordered by the study investigator or when required by the study plan. They are not used at the request of the participant. Part A There will be about 60 blood draws for dosing groups 1, 2, and 4, and 23 for dosing group 3 during the study. The total amount of blood drawn during the study for dosing groups 1, 2, and 4 is about 545 mL. This is equal to about a little more than 18½ oz or about a little more than 2¼ cups. The total amount blood drawn during the study for dosing group 3 is about 190 mL. This is equal to about a little more than 6¼ oz or about a little more than ¾ of a cup. Part B There will be about 46 59 blood draws during the study. The total amount of blood drawn during the study will be is about 540 480 mL. This is equal to about a little more than 18¼ 16 oz or about a little more than 2¼ cups Part C There will be about 34 blood draws during the study. The total amount of blood drawn during the study will be about 200 mL. This is equal to about a little more than 6¾ oz about a little more than ¾ of a cup2 cups. For comparison, the standard blood donation is about 16 oz. (2 cups), once in any 56-day period. As with all studies with blood draws, rest, hydration, rest and good eating habits are recommended. Blood loss in this amount (Part A, dosing groups 1, 2 and 4, and Part B only) may lead to a low red blood cell count (anemia). Anemia can make you feel more tired than usual. Possible Risks and Discomforts Taking part in this study has some risks. The study drug or procedure(s) may make you feel unwell or uncomfortable or could harm you. If you do not understand what any of the side effects described below mean, please let us know. The study investigator or study staff will explain them to you. It is important that you report all side effects that you have as soon as they occur. This is regardless of whether or not you believe they are caused by the study drug or your participation in this study. If you are not honest about any side effects that you have during the study, you may be harmed by staying in the study. Study Drug Risks During this study, you may receive either placebo and/or the study drug. The study drug is not expected to cause significant safety issues at the dose levels planned in this study. You may experience risks or discomforts when taking part in this study, and a summary of potential risks and discomforts will be provided to you (see below). You may also experience risks or discomforts that are unknown at this time. The study drug has been given to rats and monkeys for up to 2 weeks. While animal studies do not always predict the side effects that people may experience, the data that has been collected on the study drug to date are summarized here. All noteworthy findings in these animal studies were seen at much higher blood concentrations of study drug than may be tested in this clinical study. The study staff will be carefully monitoring your health and watching for these types of events. There were no noteworthy effects in the 2-week study in rats. In the 2-week study in monkeys, at a dose level that is similar to the highest dose that you may receive in this clinical study, some of the animals experienced the following: • Ate less food and lost weight • Vomited occasionally • Had soft feces These did not affect the health of the monkeys. There were changes in blood and chemical laboratory tests. These were not considered to be serious as the changes were small, and because there were no negative clinical effects. At the highest dose in monkeys, which was about 2 times higher than the maximum possible dose that anyone may receive in this study, the animals lost a greater amount of weight. At this high dose, the following were also seen: • Larger changes in blood and chemical laboratory tests • Some changes in the liver and kidney were seen under a microscope • This was not seen in all animals in this dose group This means that, at the highest dose, there was some injury to parts of the kidney, and corresponding decreases in kidney function were seen in the blood tests. There was also injury to some parts of the liver, and corresponding changes in liver function blood tests were seen. The study investigator will be monitoring your blood and urine samples and carefully monitoring your health throughout the study. Across all dose levels in monkeys, a few animals had minor red or pink discoloration of their skin after about 11 days of daily oral dosing with the study drug that was not considered serious. In a study focused on cardiovascular safety (heart health), where monkeys received study drug, there were no changes in heart rate or blood pressure, even at high doses. There were small changes in an ECG measurement (called QTc), but these changes were not considered serious. At the starting dose for this clinical study, the level of study drug in your blood is expected to be at least 285 times lower than the dose tested in monkeys where no significant negative effects were seen. At the maximum dose that may be tested in this study, the level of study drug in your blood will not be expected to be higher than at the dose tested in monkeys where no significant negative effects were seen. There is a possible risk of skin irritation from UV light exposure when taking the study drug. This has not been evaluated in animals. You will be asked to take precautions including avoiding tanning and prolonged sun exposure and should wear sunscreen. Midazolam Risks The most common side effects of midazolam liquid include: • Nausea • Vomiting • Dizziness • Drowsiness Midazolam may cause serious side effects including: • Hives • Difficulty breathing • Swelling of the face, lips, tongue, or throat • Severe dizziness • Mood changes • Agitation • Aggressive behavior • Uncontrollable movements • Shaking or tremor • Slow or fast heartbeat • Vision changes • Blurred vision • Fainting • Itching • Rash • Rapid, slow, or shallow breathing When you take more than one drug at a time, side effects can be more or different than if you take either drug by itself Until you know how the study drugs will affect you, you should use caution by: • Avoiding stairs • Not driving a car • Not swimming or bathing in a tub • Not working with machinery or at heights Other Risks Because the study drug is investigational, all of its side effects are not known. There may be rare and unknown side effects. These include reactions that may be life-threatening. All drugs have a potential risk of an allergic reaction. If an allergic reaction is not treated quickly, it could become life-threatening. You should get medical help right away (by calling 911 or immediately going to an emergency room) if you think you have any of the following symptoms: • Trouble breathing • Wheezing • Difficulty swallowing • Swelling of the face, mouth, lips, gums, tongue, or neck Other allergic reactions may include: • Itchiness • Rash • Hives • Blisters • Palpitations (racing heart) • Chest discomfort/tightness • Muscle pains/stiffness At times, the following may also be symptoms of an allergic reaction: • Diarrhea • Nausea • Vomiting • Abdominal pain If a significant side effect occurs, the following may be done: • Tests or treatment may be given as needed for your safety • Depending on how severe your symptoms are, you may be seen by outside medical providers or a hospital. This would be for further evaluation and/or treatment • The study investigator may notify your emergency contact as appropriate in the event of an emergency while you are taking part in the study Additional Risks or Discomforts Testing of DNA and/or RNA (deoxyribonucleic acid and/or ribonucleic acid) Genes are pieces of DNA that give coded instructions for the body. Parts of the code are passed down from parents to their children. The genes in your samples may be studied. This may include analyzing all of your genetic information. This is called “whole genome sequencing.” While collection of genetic information does not expose you to physical risk, collection of such information may result in a loss of your privacy if your genetic information is lost or stolen. There is a very small chance that your genetic information could be misused by people not involved with the research, including to discriminate against you. However, steps are in place to prevent a particular result from being linked to you and to prevent unauthorized people from even knowing genetic research was done. U.S. federal law prohibits discrimination in health insurance coverage and employment based on a person’s genetic data. However, U.S. federal law does not protect against discrimination when you are applying for: • Life insurance • Long term care insurance • Disability insurance You should talk to your physician or genetic counselor about the potential for genetic discrimination. The results of tests on your sample(s) will not be given to: • You • The study investigator • Any insurance company • Your employer • Your family • Any physician who treats you Blood Samples and IV Catheters (if used) Possible side effects of having your blood drawn or an IV catheter inserted include: • Bleeding at the site of the needle puncture • Bruising • Feeling faint • Rarely, infection or blood clot • Redness of the vein • Inflammation of the vein • Swelling • Pain • Nerve damage • Vein irritation from the fluid or medication being given • Local swelling due to IV fluid accidentally entering the tissue rather than the vein • Scarring If you feel faint, tell one of the study staff immediately.

During the Study. The events below will take place throughout the study. If you would like to know when exactly these will take place, please ask the study staff. • You will be asked about any updates to your medical history. This includes medication, drug, alcohol, and tobacco use • Physical exams, including skin neurological exam o Photographs of the skin may be taken (to see if the study clinician thinks it your nervous system is needed. Photographs are photographic images of the skin that the study team may take of you during the study. You will not be identified in these photographs. Howevernormal), if you have any markings on the area of your skin photographed, like a tattoo, those markings may appear in the photographs. Pfizer will own these photographs. The photographs and focused clinical exams to check for blood clots (Part A only) • Weight will be used and shared along with your study records, as described in this consent document. In addition, the photographs may be used in publications, presentations, brochures, or other ways. The photographs may be used along with text, graphics, or audio materials. You will not be identified by name in any use of the photographs. By signing this consent document, you are giving permission for the study staff to take these types of photographic images and for the uses described above. measured • The use of proper birth control will be confirmed/reviewed (males only) • Xxxxx xxxxx, including breathing rate (Part A only), will be measured. Your oral temperature may also be measured • Weight will be measured (Part B only) • ECGs will be collected o It may be necessary to shave or trim hair on your chest so that the patches for the ECGs will stick to your skin o Your chest may be marked with a pen to identify the correct areas for ECG patch placement • Continuous heart monitoring will be done for at least 8 hours after each dose morning dosing on Days -1, 7, 10 and 14 (Part A only, except for Japanese dosing group, if done). There will also be a period of at least 2 hours (Day -1, Period 1 only) where monitoring will be done before the first dose dosing o This involves the attachment of a small box like unit (transmitter) to your chest o The box is attached by a few wires (similar to those of an ECG) o The monitor sends information about your heart’s activity by a radio signal to a monitor o You may not sleep during the 2 hours of continuous monitoring done before dosing o You will need to stay in the procedure room for at least 4 hours after dosing while attached to the monitor o You will need to keep the box with you during the monitoring period o You will be asked to minimize activity while attached to the monitor • You will be asked: “How do you feel?” each day • An intravenous (IV) catheter may be placed in a vein in one of your arms for blood collection • OGTTs will be done (Part A [non-Japanese participants only] and B only) • The study investigator may decide to do an alcohol breath test at any time • You may complete a COVID-19 questionnaire • You may be tested for COVID-19 • Blood and urine samples will be collected at various times throughout the study o Safety Labs: The blood and urine samples will be used for safety labs including the following: ▪ Urine samples to test for drugs of abuse ▪ Blood tests to see if you may be at higher risk for Fibrinogen ▪ Blood tests for PT/INR/aPTT ▪ Blood tests for lipid panel, amylase, lipase, TSH, and free T4 having or developing a blood clot (Part B A only) o Any leftover urine, serum or plasma (components of blood) taken during from the study safety lab samples may be stored and used to assess exploratory safety biomarkers or unexpected safety findings or for other exploratory purposes, including genetic analysis ▪ Biomarkers are natural substances in your body that can be used to show how your body works ▪ Samples to be used for this purpose will be kept for up to 1 year following completion of this study o Study Drug Levels: Blood Blood, urine, and feces (urine (and feces collection for Part B B, Dosing Sequence 1, Period 1 only, all samples collected for the entire study period) samples will also be used to measure the levels of study drug and midazolam study drug-related material (Part C B only). Blood samples from Part B will also be used for metabolite profiling. The samples will also be used to evaluate safety aspects related to any concerns during or after the study ) ▪ As part of understanding how your body absorbs, distributes, and gets rid of the study drug, the samples may also be used for the following: ⮚ Metabolite identification ⮚ Metabolite profiling (Part A, Groups 2 and 4 – 7, and possibly optional groups 8 and 9, and Part B) ✓ Metabolite profiling involves identifying and measuring specific metabolites that originate in the body ⮚ Evaluate safety aspects related to any concerns during or after the study ⮚ Check the laboratory test which measures the study drug ⮚ Other internal exploratory purposes o BiomarkersPharmacodynamics: Blood samples will also be used to measure biomarkers ▪ Cholesterol determine how your body responds to the study drug (part B and C Part A only) ▪ BCAA ▪ BCKA ▪ Blood samples may also be used for the following: ⮚ Metabolite identification ⮚ Evaluate safety aspects related to any concerns during or after the study ⮚ Check the laboratory test which measures the study drug ⮚ Other internal exploratory purposes o Other: Urine samples may also be used to measure (Part A only): ▪ Pyridoxic acid (PDA) (a metabolite of Vitamin B6) Blood samples may also be used to measure (Part A only): ▪ PDA ▪ 4β-hydroxycholesterol (part B and C onlya form of cholesterol) ▪ Cholesterol ▪ CP-I (Part B only) ▪ OGTT biomarkers (Part A [non-Japanese participants] and B only) ⮚ Plasma glucose ⮚ Serum insulin and C-peptide ⮚ GLP-1, GIP, Glucagon (Part B only) Biomarker samples may also be used to: ▪ Evaluate safety or efficacy (ability to produce a desired or intended effect) aspects related to any concerns arising during or after the study ▪ Check the laboratory tests which measure the biomarkers ▪ Other internal exploratory purposes o Retained Research Samples: Samples breakdown product of your blood will be collected, stored, and used to learn more about the study drug ▪ Biological substances in your samples, including your genes and biomarkers, may be studied ▪ These samples may be kept by Pfizer for as long as the samples are useful for scientific research. This may be for many years (no time limit) • You will return to the CRU for a follow-up visit about 7 days after the last dose • You will receive a follow-up phone call about 4 weeks after the last dose • For safety reasons we may add procedures at any time during the study to check on your health status Blood Draws Blood samples will be taken by individual needlesticks, or by a catheter. A catheter is a small tube that is placed in a vein in your arm to take blood when required. Catheters are used when ordered by the study investigator or when required by the study plan. They are not used at the request of the participant. Part A There will be about 60 blood draws for dosing groups 1, 2, and 4, and 23 for dosing group 3 during the study. The total amount of blood drawn during the study for dosing groups 1, 2, and 4 is about 545 mL. This is equal to about a little more than 18½ oz or about a little more than 2¼ cups. The total amount blood drawn during the study for dosing group 3 is about 190 mL. This is equal to about a little more than 6¼ oz or about a little more than ¾ of a cup. Part B There will be about 46 blood draws during the study. The total amount of blood drawn during the study will be about 540 mL. This is equal to about a little more than 18¼ oz or about a little more than 2¼ cups Part C There will be about 34 blood draws during the study. The total amount of blood drawn during the study will be about 200 mL. This is equal to about a little more than 6¾ oz about a little more than ¾ of a cup. For comparison, the standard blood donation is about 16 oz. (2 cups), once in any 56-day period. As with all studies with blood draws, rest, hydration, and good eating habits are recommended. Blood loss in this amount (Part A, dosing groups 1, 2 and 4, and Part B only) may lead to a low forming red blood cell count (anemiacells). Anemia can make you feel more tired than usual. Possible Risks and Discomforts Taking part in this study has some risks. The study drug or procedure(s) may make you feel unwell or uncomfortable or could harm you. If you do not understand what any of the side effects described below mean, please let us know. The study investigator or study staff will explain them to you. It is important that you report all side effects that you have as soon as they occur. This is regardless of whether or not you believe they are caused by the study drug or your participation in this study. If you are not honest about any side effects that you have during the study, you may be harmed by staying in the study. Study Drug Risks During this study, you may receive either placebo and/or the study drug. The study drug is not expected to cause significant safety issues at the dose levels planned in this study. You may experience risks or discomforts when taking part in this study, and a summary of potential risks and discomforts will be provided to you (see below). You may also experience risks or discomforts that are unknown at this time. The study drug has been given to rats and monkeys for up to 2 weeks. While animal studies do not always predict the side effects that people may experience, the data that has been collected on the study drug to date are summarized here. All noteworthy findings in these animal studies were seen at much higher blood concentrations of study drug than may be tested in this clinical study. The study staff will be carefully monitoring your health and watching for these types of events. There were no noteworthy effects in the 2-week study in rats. In the 2-week study in monkeys, at a dose level that is similar to the highest dose that you may receive in this clinical study, some of the animals experienced the following: • Ate less food and lost weight • Vomited occasionally • Had soft feces These did not affect the health of the monkeys. There were changes in blood and chemical laboratory tests. These were not considered to be serious as the changes were small, and because there were no negative clinical effects. At the highest dose in monkeys, which was about 2 times higher than the maximum possible dose that anyone may receive in this study, the animals lost a greater amount of weight. At this high dose, the following were also seen: • Larger changes in blood and chemical laboratory tests • Some changes in the liver and kidney were seen under a microscope • This was not seen in all animals in this dose group This means that, at the highest dose, there was some injury to parts of the kidney, and corresponding decreases in kidney function were seen in the blood tests. There was also injury to some parts of the liver, and corresponding changes in liver function blood tests were seen. The study investigator will be monitoring your blood and urine samples and carefully monitoring your health throughout the study. Across all dose levels in monkeys, a few animals had minor red or pink discoloration of their skin after about 11 days of daily oral dosing with the study drug that was not considered serious. In a study focused on cardiovascular safety (heart health), where monkeys received study drug, there were no changes in heart rate or blood pressure, even at high doses. There were small changes in an ECG measurement (called QTc), but these changes were not considered serious. At the starting dose for this clinical study, the level of study drug in your blood is expected to be at least 285 times lower than the dose tested in monkeys where no significant negative effects were seen. At the maximum dose that may be tested in this study, the level of study drug in your blood will not be expected to be higher than at the dose tested in monkeys where no significant negative effects were seen. There is a possible risk of skin irritation from UV light exposure when taking the study drug. This has not been evaluated in animals. You will be asked to take precautions including avoiding tanning and prolonged sun exposure and should wear sunscreen. Midazolam Risks The most common side effects of midazolam liquid include: • Nausea • Vomiting • Dizziness • Drowsiness Midazolam may cause serious side effects including: • Hives • Difficulty breathing • Swelling of the face, lips, tongue, or throat • Severe dizziness • Mood changes • Agitation • Aggressive behavior • Uncontrollable movements • Shaking or tremor • Slow or fast heartbeat • Vision changes • Blurred vision • Fainting • Itching • Rash • Rapid, slow, or shallow breathing When you take more than one drug at a time, side effects can be more or different than if you take either drug by itself Until you know how the study drugs will affect you, you should use caution by: • Avoiding stairs • Not driving a car • Not swimming or bathing in a tub • Not working with machinery or at heights Other Risks Because the study drug is investigational, all of its side effects are not known. There may be rare and unknown side effects. These include reactions that may be life-threatening. All drugs have a potential risk of an allergic reaction. If an allergic reaction is not treated quickly, it could become life-threatening. You should get medical help right away (by calling 911 or immediately going to an emergency room) if you think you have any of the following symptoms: • Trouble breathing • Wheezing • Difficulty swallowing • Swelling of the face, mouth, lips, gums, tongue, or neck Other allergic reactions may include: • Itchiness • Rash • Hives • Blisters • Palpitations (racing heart) • Chest discomfort/tightness • Muscle pains/stiffness At times, the following may also be symptoms of an allergic reaction: • Diarrhea • Nausea • Vomiting • Abdominal pain If a significant side effect occurs, the following may be done: • Tests or treatment may be given as needed for your safety • Depending on how severe your symptoms are, you may be seen by outside medical providers or a hospital. This would be for further evaluation and/or treatment • The study investigator may notify your emergency contact as appropriate in the event of an emergency while you are taking part in the study Additional Risks or Discomforts Testing of DNA and/or RNA (deoxyribonucleic acid and/or ribonucleic acid) Genes are pieces of DNA that give coded instructions for the body. Parts of the code are passed down from parents to their children. The genes in your samples may be studied. This may include analyzing all of your genetic information. This is called “whole genome sequencing.” While collection of genetic information does not expose you to physical risk, collection of such information may result in a loss of your privacy if your genetic information is lost or stolen. There is a very small chance that your genetic information could be misused by people not involved with the research, including to discriminate against you. However, steps are in place to prevent a particular result from being linked to you and to prevent unauthorized people from even knowing genetic research was done. U.S. federal law prohibits discrimination in health insurance coverage and employment based on a person’s genetic data. However, U.S. federal law does not protect against discrimination when you are applying for: • Life insurance • Long term care insurance • Disability insurance You should talk to your physician or genetic counselor about the potential for genetic discrimination. The results of tests on your sample(s) will not be given to: • You • The study investigator • Any insurance company • Your employer • Your family • Any physician who treats you Blood Samples and IV Catheters (if used) Possible side effects of having your blood drawn or an IV catheter inserted include: • Bleeding at the site of the needle puncture • Bruising • Feeling faint • Rarely, infection or blood clot • Redness of the vein • Inflammation of the vein • Swelling • Pain • Nerve damage • Vein irritation from the fluid or medication being given • Local swelling due to IV fluid accidentally entering the tissue rather than the vein • Scarring If you feel faint, tell one of the study staff immediately.