Clinical trial NCT04474314
Conditions: Sickle Cell Disease
Keywords: Sickle Cell Disease
Sponsor: Cardurion Pharmaceuticals, Inc.
Start date: 2020-08-13; Completion date: 2022-05-04
Enrollment: 115 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Study to Evaluate the Safety and Efficacy of IMR-687 in Subjects with Sickle Cell Disease

Detailed description:
A phase 2b, randomized, double-blind, placebo-controlled, multicenter study of subjects with sickle cell disease (SCD; homozygous sickle hemoglobin \[HbSS\], sickle-β0 \[HbSβ0\] thalassemia, or sickle-β+ \[HbSβ+\] thalassemia) to evaluate the safety and efficacy of the phosphodiesterase type 9 (PDE9) inhibitor, IMR-687, administered once daily (qd) for 52 weeks.

Arms: arm 1: Oral administration of once daily IMR-687 arm 2: Oral administration of once daily IMR-687 arm 3: Oral administration of once daily Placebo
Interventions: intervention 1: IMR-687 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral administration of once daily IMR-687 intervention 2: Oral administration of once daily Placebo

Protocol documents:
Prot_000.pdf: 
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1. 
TITLE PAGE 
PROTOCOL 
IMR-SCD-301 
 
Study Title: 
A Phase 2b Study to Evaluate the Safety and Efficacy of IMR-687 in 
Subjects with Sickle Cell Disease 
Protocol Number: 
IMR-SCD-301 
Study Phase: 
2b 
Study Drug: 
IMR-687 
US IND: 
EudraCT: 
130549 
2019-004471-39 
Indication: 
Treatment of sickle cell disease 
Sponsor: 
IMARA, Inc. 
116 Huntington Avenue, 6th Floor 
Boston, MA 02116 
Sponsor Representative: 
Kenneth M. Attie, MD 
Senior Vice President and Chief Medical Officer, IMARA 
+1 617 710 0560 
kattie@imaratx.com 
Version Number: 
5.0 
Release Date: 
17 Feb 2022 
Replaces Version: 
4.0 
Release Date: 
08 Apr 2021 
GCP Statement: 
This study is to be performed in compliance with International Council 
for Harmonization (ICH) and applicable Good Clinical Practices (GCPs) 
and federal and local regulations.  
 
Confidentiality Statement 
This document is the property of IMARA. The information in this document contains trade 
secrets and commercial information that are privileged or confidential and may not be disclosed 
without the express written permission of IMARA unless required by federal or state law or 
regulations. Any person to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you that is 
indicated as privileged or confidential. 
 


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SPONSOR’S APPROVAL
The protocol has been reviewed and approved by IMARA, Inc.
Kenneth M. Attie, MD
Senior Vice President and Chief Medical Officer
IMARA, Inc.
Date
viewed and approved by IMARA, Inc.

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INVESTIGATOR’S AGREEMENT 
 
I have read and reviewed this clinical study protocol (IMR-SCD-301), and I agree to conduct this 
study according to this protocol, to comply with its requirements subject to ethical and safety 
considerations, and to conduct this study in accordance with all Regulatory Authority 
requirements and International Council for Harmonisation (ICH) Guidelines on Good Clinical 
Practice (ICH E6[R2]). I further agree to comply with all other applicable national and local laws 
and regulations in connection with my conduct of this study, including, without limitation, all 
applicable medical information privacy rule requirements. I agree to maintain the confidentiality 
of all information received or developed in connection with this protocol. 
I understand that the sponsor may decide to suspend or terminate the study at any time for 
whatever reason; such a decision will be communicated to me in writing. Conversely, should I 
decide to withdraw from the execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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KEY ROLES AND RESPONSIBILITIES 
Emergency Contact Information 
Role in Study 
Telephone Number 
Fax Number 
Email 
Medical Monitor 
Support Center - 
North America 
+1 866 326 5053 (toll-free) 
+1 434 951 4082 (direct) 
+1 800 280 7035 (toll-free) 
+1 913 307 5751 (direct) 
imarascd301@prahs.
com 
Medical Monitor 
for Europe, 
Middle East, 
Africa, and 
Asia-Pacific 
(EMEA/APAC) 
+49 621 878 2850 
+44 203 365 6752 
imarascd301@prahs.
com 
 
Pharmacovigilance and Patient Safety (PVS): 
North America 
Phone: +1 800 772 2215 or +1 434 951 3489 
Fax: +1 888 772 6919 or +1 434 951 3482 
Email: CHOSafety@prahs.com 
 
EMEA/APAC 
Phone : +49 621 878 2154 
Fax: +44 1792 525 720 
Email: MHGSafety@prahs.com 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company:  
IMARA Inc. 
Name of Investigational Product:  
IMR-687 
Name of Active Ingredient:  
6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-
a] pyrazin-8-one 
Protocol Number: IMR-SCD-301 
Phase: 2b 
Locations: North America, Europe, 
Africa, Middle East, and Asia 
Title of Study:  
A Phase 2b Study to Evaluate the Safety and Efficacy of IMR-687 in Subjects with Sickle Cell Disease 
Study Centers:  
This study will be conducted at approximately 70 sites. 
Objectives: 
Primary Efficacy Objective: 
 
To evaluate the effect of IMR-687 versus placebo on the annualized rate of vaso-occlusive 
crises (VOCs) 
Primary Safety Objective: 
 
To evaluate the safety and tolerability of IMR-687 versus placebo 
Key Secondary Efficacy Objectives 
 
To evaluate the effect of IMR-687 versus placebo on the time to the first occurrence of a 
VOC 
 
To evaluate the fetal hemoglobin (HbF) response to IMR-687 versus placebo 
Other Secondary Efficacy Objectives 
 
To evaluate the effect of IMR-687 versus placebo on other measures of VOCs 
 
To evaluate the effect of IMR-687 versus placebo on percentage of cells positive for fetal 
hemoglobin (HbF) (% F-cells) and total hemoglobin (Hb) 
 
To evaluate the effect of IMR-687 versus placebo on biomarkers of red blood cell (RBC) 
hemolysis 
 
To evaluate the effect of IMR-687 versus placebo on quality of life (QoL) measures 
 
To evaluate the effect of IMR-687 versus placebo on biomarkers of adhesion, 
inflammation, and cardiac stress and on RBC indices 
Secondary Pharmacokinetic Objective 
 
To evaluate the pharmacokinetic (PK) exposure of IMR-687 
Exploratory Objective 
 
To evaluate the effect of IMR-687 versus placebo on renal function 
The objectives will be assessed by the endpoints described in Section 6.2 of the protocol. 


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Methodology: 
This is a phase 2b, randomized, double-blind, placebo-controlled, multicenter study of subjects aged 
18 to 65 years with sickle cell disease (SCD; homozygous sickle hemoglobin [HbSS], sickle-β0 
[HbSβ0] thalassemia, or sickle-β+ [HbSβ+] thalassemia) to evaluate the safety and efficacy of the 
phosphodiesterase type 9 inhibitor, IMR-687, administered once daily (qd) for 52 weeks. This study 
will enroll approximately 99 subjects with SCD. This study consists of a screening period (up to 
4 weeks), a double-blind treatment period (52 weeks), and a safety follow-up period (4 weeks).  
The study schematic is provided in Figure 1, and the schedule of assessments is provided in Table 1. 
Screening 
After providing documented informed consent, subjects will enter an up to 28-day screening period. 
The following information will be obtained, and procedures will be performed for all potential subjects 
at the screening visit: medical/disease history, vital signs, electrocardiogram (ECG), complete physical 
examination (PE), laboratory tests (including safety, specialty hematology, and pharmacodynamic [PD] 
assessments). For a complete list of screening procedures, refer to the schedule of assessments. 
Treatment Period 
Subjects will receive either IMR-687 (lower dose [≥3.4 to ≤5.0 mg/kg; administered as either 200 or 
300 mg] or higher dose [>5.0 to ≤6.7 mg/kg; administered as either 300 or 400 mg]) or placebo in a 
blinded fashion. Initially, subjects will be randomly assigned in a 2:1 ratio to receive either IMR-687 
lower dose or placebo. Prior to the introduction of IMR-687 higher dose, the Data Monitoring 
Committee (DMC) will review safety data for at least 5 subjects who received IMR-687. If the DMC 
recommends inclusion of the higher dose, randomization will then proceed in a 1:2:1 ratio (IMR-687 
lower dose, IMR-687 higher dose, or placebo). During study conduct under Protocol Version 3.0, the 
DMC approved the opening of enrollment in the higher dose IMR-687 group, which went into effect 
on 12 March 2021. 
Subjects may or may not be concomitantly receiving a stable dose of hydroxyurea (HU) according to 
the subject’s established treatment plan. Randomization will be stratified by use of HU and by region. 
Subjects will return to the investigational site at Week 1 for a safety assessment, and qualified site 
personnel will contact the subject by telephone at Week 2 and Week 6 to capture potential adverse 
events (AEs) and concomitant medications.  
Subjects will be seen at the investigational site approximately every 4 weeks through Week 24, then 
every 6 weeks through Week 36, and then every 8 weeks through Week 52 (end of treatment [EOT]), 
with a safety follow-up visit at Week 56 (end of study [EOS]). Safety will be monitored throughout the 
study, and PK, PD, QoL, and clinical outcome measures will be performed at the visits shown in the 
schedule of assessments for (Table 1, in the protocol). QoL assessments include the Adult Sickle Cell 
Quality of Life Measurement Information System (ASCQ-Me®), Patient-Reported Outcomes 
Measurements Information System - Preference (PROMIS® 29 + 2 Profile v2.1 [PROPr]), and Sickle 
Cell Self-Efficacy Scale (SCSES). 
Open-label Extension 
Subjects who complete treatment (Week 52) in this study may be eligible to enroll in a planned open-
label extension (OLE) study. The EOS safety follow-up visit (Week 56) will not be expected for 
subjects who directly roll over to the OLE study. 


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Sample Size Calculation: 
The sample size of this study was previously determined based on HbF responder rate, comparing the 
highest tolerated dose of IMR-687 to placebo, as the primary endpoint: 
The sample size was determined assuming that the percentage of subjects who are HbF responders 
(i.e., have an HbF increase of ≥3% from baseline) at Week 24 is 5% in the placebo arm and 35% in 
either of the IMR-687 arms, with a 20% dropout rate prior to Week 24. Based on these assumptions, 
26 subjects/arm at Week 24 is sufficient to achieve 80% power to detect a difference between the 
highest tolerated IMR-687 dose and placebo in HbF responders at Week 24 at a 2-sided significance 
level of 0.05. 
Based on regulatory feedback, annualized rate of VOCs was elevated from a key secondary endpoint to 
the primary endpoint, with a corresponding change in statistical methodology: 
Assuming that the actual data distribution is normal when the significance level (alpha) of the test is 
0.05, the standard deviation is 2.7 in both groups, and there are no dropouts, there will be 88% power 
to detect a difference between the medians of 5.0 and 3.0 for the placebo and the IMR-687 highest 
tolerated dose groups, respectively (i.e., a 40% difference), using a 2-sided Wilcoxon rank-sum test.   
Number of Subjects (Planned):  
A total of approximately 99 adult subjects are expected to enroll in this study. 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
Each subject must meet all the following criteria to be enrolled in the study: 
1. Male or female aged ≥18 to ≤65 years at the time of informed consent form (ICF) signing. 
2. Confirmed diagnosis of SCD (HbSS, HbSβ0 thalassemia, or HbSβ+ thalassemia) in the medical 
record; if not available, the diagnosis must be confirmed at the site’s local laboratory instead. 
3. Subjects must have had at least 2 and no more than 12 documented episodes of VOC in the 
past 12 months at the time of ICF signing and at randomization (Day 1). 
For study eligibility, VOC is defined as a documented episode of an acute painful crisis (for 
which there was not an explanation other than VOC) that involved moderate to severe pain 
lasting for at least 2 hours and at least one of the following: 
 
Use of escalated analgesia (including healthcare professional-instructed use of an analgesic 
prescription) 
 
A hospital, emergency department, or clinic visit and/or healthcare telephone consultation 
at the time of occurrence 
 
Diagnosis of acute chest syndrome (ACS) (defined as an acute illness characterized by 
fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest 
X-ray), hepatic sequestration, splenic sequestration, or priapism (in males) 
4. Hb of >5.5 and <10.5 g/dL; Hb values within 21 days post-transfusion will be excluded. 
5. This inclusion criterion has been removed. 
6. Subjects receiving HU must have received it continuously for at least 6 months prior to signing 
the ICF, and must have been on a stable dose for at least 3 months prior to signing the ICF, 
with no anticipated need for dose adjustments during the study including the screening period, 
in the opinion of the investigator. 


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7. Female subjects must not be pregnant or breastfeeding and be highly unlikely to become 
pregnant. Male subjects must be unlikely to impregnate a partner. Male or female subjects 
must meet at least one of the following criteria: 
 
A female subject who is not of reproductive potential is eligible without requiring the use 
of contraception. A female subject who is not of reproductive potential is defined as one 
who: (1) has reached natural menopause (defined as 12 months of spontaneous amenorrhea 
without an alternative medical cause, and can be confirmed with serum follicle-stimulating 
hormone levels in the postmenopausal range as determined by the central laboratory); 
(2) is 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy; or 
(3) has undergone bilateral tubal ligation. Spontaneous amenorrhea does not include cases 
for which there is an underlying disease that causes amenorrhea (e.g., anorexia nervosa). 
 
A female of reproductive potential must have 2 negative pregnancy tests as verified by the 
investigator prior to starting study therapy. She must agree to ongoing pregnancy testing 
during the course of the study, at the EOT visit, and at the EOS visit. This applies even if 
the subject practices true abstinence from heterosexual contact. 
 
A male subject who is not of reproductive potential is eligible without requiring the use of 
contraception. A male subject who is not of reproductive potential is defined as one who 
has undergone a successful vasectomy. A successful vasectomy is defined as 
(1) microscopic documentation of azoospermia or (2) a vasectomy more than 2 years ago 
with no resultant pregnancy despite sexual activity post-vasectomy. 
 
A male or female subject who is of reproductive potential agrees to remain truly abstinent 
or use (or have their partner use) acceptable methods of highly effective contraception 
starting from the time of consent through 3 months after the completion of study drug. 
True abstinence is defined as abstinence that is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of the study, and 
withdrawal are not acceptable methods of contraception. Acceptable methods of highly 
effective birth control are combined or progesterone-only hormonal contraception that is 
associated with inhibition of ovulation, intrauterine device, and intrauterine 
hormone-releasing system.  
8. Be capable of giving informed consent and reading and signing the ICF after the nature of the 
study has been fully explained by the investigator or investigator designee. 
9. Be willing and able to complete all study assessments and procedures and to communicate 
effectively with the investigator and site staff. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Hospital discharge for sickle cell crisis or other vaso-occlusive event within the 4 days prior to 
randomization (Day 1). 
2. Subjects participating in a chronic/prophylactic RBC transfusion program (i.e., regularly 
scheduled RBC transfusions); any transfusions within 21 days of screening or baseline Hb 
measurements. 


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3. Subjects with HbF >25% at screening. 
4. Subjects with known active hepatitis A, hepatitis B, or hepatitis C, with active or acute event of 
malaria, or who are known to be positive for human immunodeficiency virus (HIV). 
5. For female subjects of childbearing potential, a positive serum human chorionic gonadotropin 
(hCG) test (screening) or a positive urine hCG test at randomization (Day 1). 
6. Significant kidney disease as indicated by, for example, estimated glomerular filtration rate 
(eGFR) <45 mL/min as calculated by the equation from the Modification of Diet in Renal 
Disease (MDRD) Study using creatinine, age, sex, and ethnicity (modified MDRD formula). 
7. Alanine aminotransferase or aspartate aminotransferase >3× the upper limit of normal. 
8. Body mass index (BMI) <17.0 kg/m2 or >35 kg/m2; or total body weight <45 kg.  
9. Current or history of malignancies (solid tumors and hematological malignancies), unless the 
subject has been free of the disease (including completion of any active or adjuvant treatment 
for prior malignancy) for ≥5 years. However, subjects with the following history of/concurrent 
conditions are allowed if, in the opinion of the investigator, the condition has been adequately 
diagnosed and is determined to be clinically in remission, and the subject’s participation in the 
study would not represent a safety concern: 
a. Basal or squamous cell carcinoma of the skin 
b. Carcinoma in situ of the cervix 
c. Carcinoma in situ of the breast 
d. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, 
metastasis clinical staging system) 
10. History of a clinically significant allergic reaction or hypersensitivity, as judged by the 
investigator, to any drug or any component of the study drug formulations used in the study 
(see the Investigator’s Brochure). 
11. History of unstable or deteriorating cardiac or pulmonary disease within 6 months before 
signing the ICF, including but not limited to the following:  
a. Unstable angina pectoris or myocardial infarction or elective coronary intervention  
b. Congestive heart failure requiring hospitalization  
c. Uncontrolled clinically significant arrhythmias 
12. Any condition affecting drug absorption, such as major surgery involving the stomach or small 
intestine (prior cholecystectomy is acceptable). 
13. On ECG testing at ICF signing and/or randomization (Day 1), a corrected QT interval, 
Fridericia’s formula (QTcF) >450 ms in men and >470 ms in women on 2 or more of the 
triplicate ECGs, or the presence of clinically significant ECG abnormalities as determined by 
the investigator. 
14. Major surgery within 8 weeks or minor surgery within 2 weeks of randomization (Day 1). 
15. Stroke requiring medical intervention within 24 weeks prior to randomization (Day 1). 
16. Subjects taking direct acting oral anti-coagulants (apixaban, dabigatran, rivaroxaban, 
edoxaban, or ticagrelor) or taking warfarin, unless they stopped the treatment at least 28 days 


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prior to randomization (Day 1); low molecular weight heparins are allowed in the 
peri-operative period; aspirin use (<100 mg per day) is allowed before and during the study. 
17. Poorly controlled diabetes mellitus in the opinion of the investigator, for example 
1) Hb A1c >9.0% within 12 weeks prior to randomization (in the medical history); 
2) short-term hyperglycemia leading to hyperosmolar or ketoacidotic crisis; and/or 3) history 
of diabetic cardiovascular complications. 
18. Subject has received chronic systemic glucocorticoids within 12 weeks prior to randomization 
(≥5 mg/day prednisone or equivalent). Physiologic replacement therapy for adrenal 
insufficiency is allowed. 
19. Any clinically significant bacterial, fungal, parasitic, or viral infection requiring antibiotic 
therapy should delay screening/randomization (Day 1) until the course of antibiotic therapy has 
been completed. This includes, but is not limited to, long-term tuberculosis treatment. 
20. Participated in another clinical study of an investigational agent (or medical device) within 
30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently 
participating in another study of an investigational agent (or medical device).  
21. Prior exposure to IMR-687. 
22. History of crizanlizumab (Adakveo®) or voxelotor (Oxbryta®) use within 6 months prior to 
signing the ICF or anticipated need for such agents during the study. 
23. Consumption/use of the following drugs or other substances within the specified time periods 
before randomization or plans to consume/use at any time during the study. If there is any 
question as to whether a substance is permitted, please review the product labeling (if 
applicable) and consult the medical monitor and/or sponsor. 
a. Phosphodiesterase type 5 inhibitors (including but not limited to sildenafil, tadalafil, and 
vardenafil) within 7 days prior to randomization (Day 1) or plans to use during the study. 
b. Grapefruit, grapefruit juice, grapefruit products, or herbal supplements with CYP-altering 
abilities within 1 week prior to randomization (Day 1) or plans to consume during the 
study. 
c. CYP3A-sensitive substrates, including the opioids fentanyl and alfentanil, or moderate to 
strong CYP3A inhibitors or inducers within 28 days prior to randomization (Day 1) or 
plans to use during the study 
d. Any drugs or substances known to be substrates or inhibitors of P-glycoprotein or breast 
cancer resistance protein within 28 days prior to randomization (Day 1) or plans to use 
during the study. 
24. Receipt of erythropoietin, luspatercept (Reblozyl®), or other erythropoiesis-stimulating or 
erythroid maturation agent within 6 months prior to signing the ICF or anticipated need for 
such agents during the study. 
25. Prior gene therapy. 
26. Any significant medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from participating in the study, including the presence of laboratory 
abnormalities that may place the subject at unacceptable risk if he/she were to participate in the 
study. 


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27. Other prior or ongoing medical condition, physical findings, or laboratory abnormality that, in 
the investigator’s opinion, could adversely affect the safety of the subject, make it unlikely that 
the course of treatment or follow-up would be completed, or impair the assessment of study 
results (e.g., a history of drug or alcohol abuse within the past 1 year, as judged by the 
investigator). 
Investigational Product, Dosage, and Mode of Administration:  
IMR-687 will be supplied as 100, 150, or 200 mg white tablets. Subjects will be advised to take 
2 tablets orally, qd. The different doses of IMR-687 are visually identical. Subjects will be directed to 
take their study drug with food. 
Reference Therapy, Dosage, and Mode of Administration:  
Placebo will be supplied as white tablets containing matrix absent IMR-687. The placebo tablets are 
visually identical to the IMR-687 tablets. Subjects will be advised to take 2 tablets orally, qd. Subjects 
will be directed to take their study drug with food. 
Duration of Treatment: 
The maximum treatment duration for a given subject is 52 weeks. 
Assessments: 
For both safety and efficacy evaluations, laboratory tests specified in the protocol will be performed by 
a central laboratory. Because knowledge of certain laboratory assessments (HbF, % F-cells, mean 
corpuscular volume [MCV], total and unconjugated [indirect] bilirubin, and absolute and 
% reticulocyte count) may unblind the treatment assignment, these measurements will be blinded at the 
central laboratory. Based on predefined safety laboratory alerts, these blinded laboratory assessments 
may be communicated to the investigator. 
Safety 
Safety assessments include vital signs, weight, ECGs, evaluation of clinical laboratory parameters, 
AEs, concomitant medications, and PEs. 
Efficacy and Pharmacodynamics 
Efficacy and PD assessments include laboratory measurements based on blood samples 
(HbF-associated biomarkers and Hb; biomarkers of RBC hemolysis, adhesion, inflammation, and 
cardiac stress; RBC indices); clinical outcome measures (VOCs and related parameters); and QoL 
measures (ASCQ-Me®, PROPr, and SCSES). 
Pharmacokinetics 
PK assessments include IMR-687 plasma concentration measurements from blood samples that will be 
collected pre-dose and serially up to 3 hours post-dose on Day 1 and at Week 4 visits; additional trough 
samples will be collected pre-dose at Week 24 and on the last day of dosing (Week 52). 
Statistical Methods: 
Primary Efficacy Analysis 
The primary efficacy endpoint, annualized rate of VOCs, will be analyzed using a stratified Wilcoxon 
rank-sum test based on stratification factors of region (North America/Europe versus Africa/Middle 
East) and HU use (Yes versus No) to compare the treatment effect of the highest tolerated dose of 
IMR-687 to placebo. VOCs are defined for this study in Inclusion Criterion 3 (Section 8.1). 
An interim analysis (IA) will be performed after all randomized subjects have reached Week 24 or 
terminated early. A Lan-DeMets alpha spending function will be used to determine the significance 
levels for the IA to maintain an overall type I error rate of 5% for 2-sided tests.  


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Secondary Efficacy Analyses 
The first key secondary efficacy endpoint, time to first VOC, will be analyzed using a stratified log 
rank test (stratification factors of HU use and region) and stratified Cox regression model to compare 
the treatment effect of the highest tolerated dose of IMR-687 to placebo.  
The second key secondary efficacy endpoint, proportion of HbF responders (defined as the proportion 
of subjects with an absolute increase of ≥3% in HbF from baseline) at Week 24, will be analyzed using 
a stratified Cochran-Mantel-Haenszel (CMH) test based on stratification factors of HU use and region 
to compare the highest tolerated dose of IMR-687 to placebo. 
Other secondary endpoints that will be tested at the highest tolerated dose include the following: 
 Proportion of VOC-free subjects 
 
Annualized rate of hospitalizations for VOCs 
 
Time to second VOC 
 
Proportion of HbF responders (defined as the proportion of subjects with an absolute increase 
of ≥3% in HbF from baseline) at Week 52 
 
Change from baseline in HbF (%) and F-cells (%) at Week 24 and Week 52 
 
Proportion of Hb responders (defined as the proportion of subjects with an increase of 
≥1.0 g/dL in total Hb from baseline) at Week 24 and Week 52 
 
Change from baseline in total Hb (g/dL) at Week 24 and Week 52 
 
Change from baseline in biomarkers of RBC hemolysis (% and absolute reticulocytes, 
unconjugated [indirect] bilirubin, and lactate dehydrogenase [LDH]) at Week 24 and Week 52 
 
Change from baseline in each measured subdomain of the ASCQ-Me® questionnaire at 
Week 24 and Week 52 
 
Change from baseline in total preference score and individual domain scores of the PROPr 
questionnaire at Week 24 and Week 52 
 
Change from baseline in overall score of the SCSES at Week 24 and Week 52 
 
Change from baseline in biomarkers of adhesion such as soluble E-selectin (E-sel), P-selectin 
(P-sel), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 
(VCAM-1) at Week 24 and Week 52 
 
Change from baseline in biomarkers of inflammation such as high-sensitivity C-reactive 
protein (hsCRP) and myeloperoxidase (MPO) at Week 24 and Week 52 
 
Change from baseline in biomarkers of cardiac stress such as N-terminal prohormone of brain 
natriuretic peptide (NT-proBNP) at Week 24 and Week 52 
 
Change from baseline in RBC indices, such as MCV, at Week 24 and Week 52 
The secondary endpoints of proportion of HbF responders at Week 52 and proportion of Hb responders 
at Week 24 and Week 52 will each be analyzed in a similar manner as the second key secondary 
efficacy endpoint using a stratified CMH test based on stratification factors of HU use and region. 
The annualized rate of hospitalizations for VOCs will be analyzed using a stratified Wilcoxon 
rank-sum test based on stratification factors of HU use and region. 


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Change from baseline endpoints for continuous variables will be analyzed using mixed models for 
repeated measures (MMRM) with treatment, visit, and treatment-by-visit interaction as fixed effects, 
and baseline value, HU use, and region as covariates. Unstructured covariance matrices will be used. 
Time-to-event endpoints will be analyzed using log-rank tests, and Kaplan-Meier plots will be 
provided. 
A final analysis (FA) will be conducted at study completion (i.e., when all subjects have reached 
Week 56 or terminated early). A Lan-DeMets alpha spending function will be used to determine the 
significance level for the IA and FA to maintain an overall type I error rate of 5% for 2-sided tests. At 
the FA, endpoints will be tested in a sequential hierarchical order at the highest tolerated dose. 
Safety Analyses 
Safety will be evaluated by the frequency of AEs and by changes from baseline in subjects’ vital signs, 
clinical laboratory results, and ECG parameters. 
Pharmacokinetic Analyses 
Summary statistics for trough (Ctrough) and other plasma concentration data will be provided. 
Accumulation may be assessed. PK data from this study will also be used to explore any relationship 
between IMR-687 exposure and clinical response, PD endpoints, or AEs, as data permit. These data 
will be analyzed together with PK data from other clinical studies for a population PK analysis, as 
appropriate.  


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TABLE OF CONTENTS 
1. 
TITLE PAGE ..................................................................................................................1 
SPONSOR’S APPROVAL ..............................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
KEY ROLES AND RESPONSIBILITIES ......................................................................................4 
2. 
SYNOPSIS ......................................................................................................................5 
TABLE OF CONTENTS ...............................................................................................................14 
LIST OF TABLES .........................................................................................................................19 
LIST OF FIGURES .......................................................................................................................19 
3. 
LIST OF ABBREVIATIONS .......................................................................................20 
4. 
INTRODUCTION ........................................................................................................24 
4.1. 
Overview of Disease Pathogenesis ...............................................................................24 
4.2. 
Overview of IMR-687 Development ............................................................................25 
4.2.1. 
IMR-687 ........................................................................................................................25 
4.2.2. 
Nonclinical Data............................................................................................................25 
4.2.3. 
Clinical Data..................................................................................................................26 
4.2.3.1. 
Phase 1a Study of IMR-687 in Healthy Adult Volunteers (IMR-SCD-101) ................26 
4.2.3.2. 
Phase 2a Study of IMR-687 in Adult Subjects with Sickle Cell Anemia 
(IMR-SCD-102) ............................................................................................................27 
5. 
RATIONALE ................................................................................................................28 
5.1. 
Study Rationale and IMR-687 Dose Rationale .............................................................28 
5.2. 
Benefit/Risk Assessment ...............................................................................................29 
5.2.1. 
Potential Benefits ..........................................................................................................29 
5.2.2. 
Potential Risks ...............................................................................................................29 
5.2.2.1. 
Gastrointestinal .............................................................................................................29 
5.2.2.2. 
Central Nervous System ................................................................................................30 
5.2.2.3. 
Cardiovascular...............................................................................................................30 
5.2.3. 
Potential Interactions .....................................................................................................30 
6. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................32 
6.1. 
Objectives ......................................................................................................................32 
6.1.1. 
Primary Efficacy Objective ...........................................................................................32 
6.1.2. 
Primary Safety Objective ..............................................................................................32 


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6.1.3. 
Key Secondary Efficacy Objectives..............................................................................32 
6.1.4. 
Other Secondary Efficacy Objectives ...........................................................................32 
6.1.5. 
Secondary Pharmacokinetic Objective .........................................................................32 
6.1.6. 
Exploratory Objective ...................................................................................................32 
6.2. 
Endpoints ......................................................................................................................32 
6.2.1. 
Primary Efficacy Endpoint ............................................................................................32 
6.2.2. 
Safety Endpoints ...........................................................................................................33 
6.2.3. 
Key Secondary Efficacy Endpoints ..............................................................................33 
6.2.4. 
Other Secondary Efficacy Endpoints ............................................................................33 
6.2.5. 
Secondary Pharmacokinetic Endpoint ..........................................................................34 
6.2.6. 
Exploratory Endpoint ....................................................................................................34 
7. 
INVESTIGATIONAL PLAN .......................................................................................35 
7.1. 
Overall Study Design ....................................................................................................35 
7.1.1. 
Screening .......................................................................................................................35 
7.1.2. 
Treatment Period ...........................................................................................................35 
7.1.3. 
Open-Label Extension ...................................................................................................36 
7.2. 
Data Monitoring Committee .........................................................................................41 
7.3. 
Number of Subjects .......................................................................................................41 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................42 
8.1. 
Subject Inclusion Criteria ..............................................................................................42 
8.2. 
Subject Exclusion Criteria.............................................................................................43 
8.3. 
Screen Failures ..............................................................................................................46 
8.4. 
Guidelines for Withdrawal of Subjects from Study Participation ................................46 
8.5. 
Guidelines for Study Drug Dose Withholding or Discontinuation ...............................47 
8.6. 
Replacement of Subjects ...............................................................................................48 
8.7. 
Stopping Rules and Study Termination ........................................................................48 
9. 
STUDY TREATMENTS ..............................................................................................50 
9.1. 
Study Drug ....................................................................................................................50 
9.2. 
Packaging and Labeling ................................................................................................50 
9.3. 
Storage Conditions ........................................................................................................50 
9.4. 
Administration ..............................................................................................................50 
9.5. 
Treatment Compliance ..................................................................................................51 
9.6. 
Concomitant Medications .............................................................................................51 


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9.6.1. 
Non-investigational Medicinal Products .......................................................................51 
9.6.2. 
Prohibited Concomitant Medications/Therapies ...........................................................51 
9.6.3. 
Prohibited Concomitant Procedures ..............................................................................52 
9.7. 
Handling and Disposal ..................................................................................................52 
10. 
RANDOMIZATION AND BLINDING .......................................................................53 
10.1. 
Randomization ..............................................................................................................53 
10.2. 
Blinding .........................................................................................................................53 
10.3. 
Unblinding for Interim Analyses ..................................................................................53 
10.4. 
Emergency Unblinding .................................................................................................53 
11. 
ASSESSMENTS ...........................................................................................................55 
11.1. 
Screening and Baseline Activities .................................................................................55 
11.1.1. 
Informed Consent ..........................................................................................................55 
11.1.2. 
Demographic Information and Medical/Disease History .............................................55 
11.1.3. 
Inclusion/Exclusion Criteria Evaluation .......................................................................56 
11.1.4. 
Height ............................................................................................................................56 
11.1.5. 
Serum Virology .............................................................................................................56 
11.2. 
Efficacy and Pharmacodynamic Assessments ..............................................................56 
11.2.1. 
Specialty Hematology ...................................................................................................56 
11.2.2. 
Pharmacodynamic Assessments ...................................................................................56 
11.2.3. 
Clinical Assessment: VOCs ..........................................................................................57 
11.2.4. 
Quality of Life Assessments .........................................................................................57 
11.3. 
Safety Assessments .......................................................................................................57 
11.3.1. 
Telephone Visits............................................................................................................57 
11.3.2. 
Vital Signs .....................................................................................................................58 
11.3.3. 
Weight ...........................................................................................................................58 
11.3.4. 
Physical Examination ....................................................................................................58 
11.3.5. 
Electrocardiogram .........................................................................................................58 
11.3.6. 
Laboratory Assessments................................................................................................59 
11.3.6.1. Hematology ...................................................................................................................59 
11.3.6.2. Coagulation ...................................................................................................................59 
11.3.6.3. Serum Chemistry ...........................................................................................................59 
11.3.6.4. Urinalysis ......................................................................................................................59 
11.3.6.5. Pregnancy Test ..............................................................................................................60 


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11.3.7. 
Adverse Event Collection .............................................................................................60 
11.3.8. 
Concomitant Medications .............................................................................................60 
11.4. 
Pharmacokinetics Assessments .....................................................................................60 
12. 
SAFETY MONITORING AND REPORTING ............................................................61 
12.1.1. 
Adverse Event and Serious Adverse Event Collection .................................................61 
12.1.1.1. Time Period Adverse Event Collection.........................................................................61 
12.1.1.2. Follow-up ......................................................................................................................61 
12.1.2. 
Adverse Event Recording and Reporting ......................................................................61 
12.1.2.1. Definitions .....................................................................................................................61 
12.1.2.2. Evaluation of Adverse Events/Serious Adverse Events................................................63 
12.1.2.3. Recording and Reporting Adverse Events and Serious Adverse Events ......................64 
12.1.2.4. Regulatory Reporting Requirements .............................................................................65 
12.1.2.5. Exposure During Pregnancy .........................................................................................65 
12.1.3. 
Medication Error and Reporting ...................................................................................66 
13. 
STATISTICS ................................................................................................................67 
13.1. 
General Considerations .................................................................................................67 
13.2. 
Analysis Datasets ..........................................................................................................67 
13.3. 
Safety Analyses .............................................................................................................68 
13.4. 
Efficacy Analyses..........................................................................................................68 
13.5. 
Pharmacokinetic Analyses ............................................................................................69 
13.6. 
Analyses of Exploratory Endpoint ................................................................................70 
13.7. 
Sample Size Calculation ...............................................................................................70 
14. 
DATA COLLECTION AND QUALITY CONTROL .................................................71 
14.1. 
Database Management and Data Quality Control .........................................................71 
14.2. 
Study Site Monitoring ...................................................................................................71 
14.3. 
Subject Data Protection and Confidentiality .................................................................72 
15. 
ADMINISTRATIVE, ETHICAL, AND REGULATORY 
CONSIDERATIONS ....................................................................................................74 
15.1. 
Protocol .........................................................................................................................74 
15.1.1. 
Protocol Amendments ...................................................................................................74 
15.1.2. 
Protocol Adherence .......................................................................................................74 
15.1.3. 
Discontinuation of Site Participation ............................................................................74 
15.1.4. 
Protocol Disclosure and Confidentiality .......................................................................74 


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15.2. 
Institutional Review Board or Independent Ethics Committee.....................................75 
15.3. 
Ethical Conduct of the Study ........................................................................................75 
15.4. 
Subject Informed Consent .............................................................................................75 
15.5. 
Publication of Study Protocol and Results ....................................................................76 
15.6. 
Correlative Studies ........................................................................................................76 
15.7. 
Investigators and Study Personnel ................................................................................76 
15.8. 
Study Documentation, Record Keeping, and Retention of Documents ........................77 
15.9. 
Audits and Inspections ..................................................................................................77 
16. 
REFERENCES ..............................................................................................................78 
17. 
APPENDICES ..............................................................................................................80 
17.1. 
Appendix 1: Lists of Potential In Vivo CYP3A Drug-Drug Interactions .....................80 
17.2. 
Appendix 2: National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE, version 5.0) .................................................................81 
 
 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................38 
Table 2: 
Safety Guidelines for Study Drug Dose Reduction, Withholding, or 
Discontinuation ...........................................................................................................47 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................37 
 


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3. 
LIST OF ABBREVIATIONS 
Abbreviation  
Definition 
%CV 
coefficient of variation 
ACS 
acute chest syndrome 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ASCQ-Me 
Adult Sickle Cell Quality of Life Measurement Information System 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
AUC from time 0 to 24 hours 
BCRP 
breast cancer resistance protein 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
cGMP 
cyclic guanosine monophosphate 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
Ctrough 
trough plasma concentration 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DMC 
Data Monitoring Committee 
DOAC 
direct acting oral anti-coagulant 
EC50 
half-maximal effective concentration 
ECG 
Electrocardiogram 
eGFR 
estimated glomerular filtration rate 
eCRF 
electronic case report form 
EOS 
end of study 
EOT 
end of treatment 


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Abbreviation  
Definition 
E-sel 
E-selectin 
ET 
early termination 
F-cells 
cells positive for HbF 
FA 
final analysis 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
Hb 
hemoglobin 
HbF 
fetal hemoglobin 
HBsAg 
hepatitis B surface antigen 
HbSβ0 
sickle-β0 hemoglobin 
HbSβ+ 
sickle-β+ hemoglobin 
HbSS 
homozygous sickle hemoglobin 
hCG 
human chorionic gonadotropin 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HED 
human equivalent dose 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
hsCRP 
high-sensitivity C-reactive protein 
HU 
hydroxyurea 
IA 
interim analysis 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
ICAM-1 
intercellular adhesion molecule 1 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 


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Abbreviation  
Definition 
IgM 
immunoglobulin M  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IXRS 
interactive voice/web response system 
LDH 
lactate dehydrogenase 
MAD 
multiple-ascending dose 
MCV 
mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease Study 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed models for repeated measures 
MPO 
myeloperoxidase 
NCI CTCAE 
National Cancer Institute Common Terminology for Adverse 
Events 
NO 
nitric oxide 
NOAEL 
no observed adverse effect level 
NT-proBNP 
N-terminal prohormone of brain natriuretic peptide 
OECD 
Organization for Economic Cooperation and Development 
OLE 
open-label extension 
P-gp 
P-glycoprotein 
PA 
primary analysis 
PD 
pharmacodynamic(s) 
PDE5 
phosphodiesterase type 5 
PDE9 
phosphodiesterase type 9 
PE 
physical examination 
PK 
pharmacokinetic(s) 
PP 
per protocol 
Pr:Cr 
protein-to-creatinine (ratio) 
PROMIS 
Patient-Reported Outcomes Measurements Information System 
PROPr 
PROMIS – Preference 
P-sel 
P-selectin 
PT 
prothrombin time 
PXR 
pregnane X receptor 


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Abbreviation  
Definition 
Q1 
first quartile 
Q3 
third quartile 
qd 
once daily 
QoL 
quality of life 
QTcF 
corrected QT interval, Fridericia’s formula 
RBC 
red blood cell 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SCD 
sickle cell disease 
SCSES 
Sickle Cell Self-Efficacy Scale 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum concentration 
US 
United States 
VCAM-1 
vascular cell adhesion molecule 1 
VOC 
vaso-occlusive crisis 
WBC 
white blood cell 


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4. 
INTRODUCTION 
4.1. 
Overview of Disease Pathogenesis 
The sponsor is developing IMR-687 for the treatment of patients with sickle cell disease (SCD) 
and β-thalassemia. The population for this study includes subjects with the following forms of 
SCD: homozygous sickle hemoglobin (HbSS), sickle-β0 (HbSβ0) thalassemia, and sickle-β+ 
(HbSβ+) thalassemia. 
With a neonatal incidence of 294,000 to 330,000 patients worldwide (Piel 2013), SCD is a rare 
inherited disorder of red blood cells (RBCs) that is both serious and life-threatening. The most 
common manifestations of SCD include vaso-occlusive crisis (VOC), chronic and acute severe 
pain, acute chest syndrome (ACS), stroke, priapism, acute anemia (particularly from aplastic 
crisis and splenic sequestration), increased susceptibility to infection, and progressive damage to 
major organs, including the spleen, brain, kidney, heart, lung, skin, retina, vestibular cochlear 
systems, and bone. In developed countries where there is prenatal screening and widespread 
access to prophylactic and acute interventions, the median age of death remains in the 40s to 50s, 
although many patients succumb to the disease much earlier (Platt 1994; Lanzkron 2013; 
Paulukonis 2016).  
SCD is caused by a specific point mutation (E6V) in the gene encoding hemoglobin (Hb) subunit 
beta that leads to the production of abnormal Hb (“sickle hemoglobin” or HbS). Under 
conditions of hypoxia, acidity, and/or dehydration, the intracellular concentration of 
deoxygenated HbS increases, which favors its polymerization and causes RBCs to deform (i.e., 
sickle) or become rigid, leading to a complex cascade of hemolysis, inflammation, elevated cell 
adhesion, leukocytosis, oxidative stress, and endothelial dysfunction that culminates in the 
vascular obstruction and ischemia responsible for much of the observed morbidity in SCD.  
Prior to July 2017, the only drug specifically approved for the treatment of SCD was 
hydroxyurea (HU), a small molecule inhibitor of ribonucleotide reductase that was originally 
developed for the treatment of myeloproliferative disorders. HU (also known as 
hydroxycarbamide) has been approved to treat SCD since 1998 in the United States (US) and 
since 2001 in Europe. In SCD, HU reduces painful crises and the need for blood transfusions 
(Charache 1995), at least in part by increasing levels of fetal hemoglobin (HbF), which reduces 
RBC sickling and improves blood flow. These effects are mediated, at least in part, by increased 
nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) production (Erard 1981; 
Platt 1984; Cokic 2003). Unfortunately, HU is often poorly tolerated, and its widespread use is 
limited by concerns about its potential impact on fertility and reproduction, challenges achieving 
and maintaining an efficacious dose due to its hematologic toxicities, and requirements for 
monthly monitoring (Heeney and Ware 2008).  
In July 2017, L-glutamine oral powder (Endari™) was approved in the US to reduce 
complications of SCD. In November 2019, crizanlizumab (Adakveo®) and voxelotor (Oxbryta®) 
were approved by the Food and Drug Administration (FDA). Crizanlizumab (Adakveo®) is a 
humanized, anti-P-selectin monoclonal antibody that reduces the frequency of VOCs in adults 
and adolescents over the age of 16 years. Voxelotor (Oxbryta®) is an oral, once daily (qd) drug 
that binds to the α-chain of HbS, stabilizing the molecule in the R-state conformation, which is 
known to interrupt HbS polymerization. Both drugs are among the new therapies targeting 


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multiple pathways in the complex pathophysiology of SCD (Ballas 2020); however, due to the 
current cost of voxelotor (Oxbryta®) and crizanlizumab (Adakveo®), these therapies may not be 
accessible globally, especially for patients in resource-poor countries. Thus, additional 
accessible, novel, safe, and effective treatments to prevent the morbid complications of SCD in 
patients of all ages are still urgently needed. 
4.2. 
Overview of IMR-687 Development 
4.2.1. 
IMR-687 
IMR-687 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-
yl-7H-imidazo[1,5-a]pyrazin-8-one) is a potent, specific, and highly selective small molecule 
inhibitor of phosphodiesterase type 9 (PDE9); PDE9 mediates cellular signaling pathways by 
degrading cGMP to its inactive or monophosphate form. 
By inhibiting PDE9, IMR-687 is intended to increase cGMP levels and thus stimulate the 
production of HbF, which reduces the cellular concentration of abnormal Hb (HbS) within RBCs 
and its associated sequelae. The importance of increasing HbF in treating SCD is evidenced by 
results from large studies like the Cooperative Study of Sickle Cell Disease in the US and studies 
in a variety of patient cohorts outside of the US showing that HbF is among the most important 
modifiers of this disease (Platt 1991; Platt 1994; Alsultan 2013), as well as data showing that 
modifiers of HbF improve other hematological parameters of SCD (Akinsheye 2011; 
Alsultan 2013; Barbosa 2013; Sheehan 2013). 
PDE9 is highly expressed in hematopoietic cells and is also widely distributed in the brain 
(Fisher 1998; Matsumoto 2003; Nagasaki 2012), with the highest expression measured in 
cerebellar Purkinje cells of rodents (van Staveren 2002). A potential advantage of IMR-687 for 
the SCD and β-thalassemia indications is that it does not readily distribute to the brain and, 
therefore, is less likely to result in the central nervous system (CNS) effects observed with other, 
brain-penetrating PDE9 inhibitors (Schwam 2014; Hutson 2011; Van der Staay 2008). 
Moreover, due to its specificity for PDE9, and the absence of evidence of genotoxicity and 
hepatotoxicity in Good Laboratory Practice (GLP) toxicology studies, IMR-687 could contribute 
to a meaningful improvement in the standard of care for patients. 
4.2.2. 
Nonclinical Data 
The IMR-687 nonclinical program supports its potential safety and efficacy for the treatment of 
SCD. 
In vitro studies have demonstrated IMR-687’s ability to increase cGMP in K562 cells and 
increase HbF in both K562 and CD36+ RBCs cultured ex vivo from blood-derived CD34+ cells 
from SCD patients, supporting IMR-687’s proposed mechanism of action. These findings were 
confirmed and extended by in vivo studies demonstrating IMR-687’s ability to increase HbF and 
reduce RBC sickling in both Berkeley and Townes sickle cell transgenic mouse models and to 
reduce the degree of microvascular stasis observed following hypoxia and re-oxygenation in 
Townes mice. Administration of 10 or 30 mg/kg IMR-687 to C57Bl/6J mice for 5 days 
demonstrated low CNS exposure, with no effect on locomotor activity or memory. 
In a series of GLP/Organization for Economic Cooperation and Development (OECD)-compliant 
safety pharmacology studies evaluating behavioral, respiratory, and cardiovascular functions, no 


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untoward adverse effects were noted. In addition, repeat-dose toxicology studies in rats (up to 6 
months) and dogs (up to 9 months) were well tolerated and provided no observed adverse effect 
levels (NOAELs) that were comfortably in excess of those to be administered to humans. 
IMR-687 had low-moderate plasma protein binding in the 5 species tested (<32%), and there was 
no notable partitioning into RBCs. IMR-687 has the potential for induction of cytochrome P450 
(CYP)3A4 (half-maximal effective concentration [EC50] = 32.4 to 133 µM). IMR-687 was not a 
competitive inhibitor of CYPs 1A2, 2B6, 3A4/5, 2C9, 2C19, 2C8, and 2D6 (half-maximal 
inhibitory concentration [IC50] >100 µM). IMR-687 is a substrate of P-glycoprotein (P-gp; Km 
>500 µM) and breast cancer resistance protein (BCRP) (Km = 45.5 µM). IMR-687 is an inhibitor 
of BCRP (IC50 = 32.5 µM), OCT1 (IC50 = 834 µM), and MATE2-K (IC50 = 441 µM). 
Fifteen metabolites have been detected (in nonclinical testing) to date. Metabolic pathways 
included dehydrogenation, hydration, and oxidation. Both renal and biliary excretion of 
14C-IMR-687-related radioactivity (as unchanged IMR-687 and metabolites) were observed in 
the rat. Metabolites found in rat hepatocytes were consistent with those observed in vivo. 
Metabolites in human hepatocytes were not unique relative to those observed in rat and dog 
hepatocytes. CYP phenotyping experiments have indicated that IMR-687 is primarily a substrate 
for CYP3A4 (Km  127 µM). Metabolites M1 and M4 result from N-dealkylation of IMR-687 
and may be major circulating metabolites.  
4.2.3. 
Clinical Data 
4.2.3.1. 
Phase 1a Study of IMR-687 in Healthy Adult Volunteers (IMR-SCD-101) 
A first-in-human, randomized, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, and pharmacokinetics (PK) of IMR-687 (capsule formulation) has been completed 
(IMR-SCD-101). The study enrolled 66 healthy male and female adults (aged 18 to 55 years, 
inclusive), of whom 16 subjects received placebo and 50 subjects received IMR-687. The study 
was divided into 3 parts: a single-ascending-dose (SAD) study (Part A), a food effect study 
(Part B), and a multiple-ascending-dose (MAD) study (Part C); all parts had oral dosing. In Part 
A, 20 subjects received single doses of IMR-687 in the fasted state. The initial planned doses 
were 0.3, 1, 3, 6, 9, and 12 mg/kg; a 4.5 mg/kg dose was added and the 9 and 12 mg/kg doses 
were removed after a dose-limiting toxicity of moderate emesis was observed at 6 mg/kg. In 
Part B, 12 subjects received 2 single doses of IMR-687 at 1 mg/kg under fed and fasting 
conditions. In Part C, 18 subjects received 7 doses of either 1, 3, or 4.5 mg/kg/day.  
IMR-687 was safe and well tolerated at doses up to 4.5 mg/kg when administered as single and 
multiple qd doses (up to 7 days) of oral capsules to healthy volunteers in a weight-based dosing 
regimen. The most frequent drug-related adverse event (AE) was nausea. In Part A (SAD study 
in the fasted state), 35% of all IMR-687 subjects experienced nausea, compared to 0% of placebo 
subjects. Nausea was mild, transient, and self-limited at doses ≤4.5 mg/kg; the incidence of 
nausea was sporadic at single doses ≤3 mg/kg IMR-687. Headaches were also a notable, likely 
drug-related treatment-emergent adverse event (TEAE), particularly in the fasted state (30% of 
all IMR-687 subjects in the SAD Part A, compared to 0% in the placebo group). 
Oral administration of IMR-687 with food significantly reduced both the incidence and severity 
of the nausea and headache TEAEs. Whereas single doses of 4.5 mg/kg IMR-687 in fasted 
subjects resulted in mild nausea in 75% of subjects, single doses of 4.5 mg/kg IMR-687 did not 


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result in nausea when given after a high-fat meal. Only after at least 6 daily doses did mild 
nausea occur with 4.5 mg/kg IMR-687 given with a meal. The incidence of headaches when 
IMR-687 was given with food was similar between IMR-687-treated (11.1%) and 
placebo-treated (16.7%) groups. 
Nausea onset was between 30 and 120 minutes after the oral administration of IMR-687 and 
generally lasted 2 to 8 hours. Together with the mitigating effects of food intake and the fact that 
IMR-687 is a P-gp substrate and unlikely to be CNS penetrant, these data are consistent with 
nausea/emesis resulting from a local effect of IMR-687 in the stomach or the gastrointestinal 
(GI) tract.  
IMR-687 administration was not associated with any clinically significant changes in laboratory 
values, physical examinations (PEs), or standard 12-lead electrocardiograms (ECGs). Of note, 
IMR-687 did not result in any significant changes in white blood cell (WBC), platelet, or 
absolute neutrophil counts. 
Exposure parameters following single or multiple qd doses of IMR-687 increased with dose in a 
near dose-proportional manner (e.g., a 4.1-fold increase for a 4.5-fold change in dose). 
Administration with food slowed the rate of absorption of IMR-687 (median time to maximum 
concentration [tmax] delayed by approximately 3 hours), which resulted in an approximately 26% 
decrease in maximum plasma concentration (Cmax), but no change in overall exposure (area 
under the concentration-time curve [AUC]). Multiple-dose PK demonstrated that IMR-687 did 
not accumulate to a significant extent in healthy volunteers (<13%). 
4.2.3.2. 
Phase 2a Study of IMR-687 in Adult Subjects with Sickle Cell Anemia 
(IMR-SCD-102) 
Study IMR-SCD-102 was a phase 2a, randomized, double-blind, placebo-controlled study in 
adult subjects with HbSS or HbSβ0 thalassemia that was completed in 2020. 
The objectives of this study were to evaluate the safety, tolerability, PK, and pharmacodynamic 
(PD) effects of IMR-687 (tablet formulation) administered for 16 to 24 weeks in 2 subject 
populations: those not on HU (Population A) and those receiving a stable dose of HU according 
to standard of care (Population B). Eligible subjects in non-HU Population A were initially 
randomized 1:1:1 to receive 50 mg IMR-687, 100 mg IMR-687, or placebo for a total of 
24 weeks. A planned interim analysis (IA) suggested that the 50 mg dose would not provide the 
exposure and efficacy needed to meet clinical outcomes, and the protocol was amended for 
subjects to receive 100 mg IMR-687 or placebo in a 2:1 randomization for 4 weeks and, if well 
tolerated, to escalate from 100 mg to 200 mg for the remaining 20 weeks of the study. Similarly, 
in stable HU Population B, subjects were randomized 2:1 to receive 50 mg IMR-687 or placebo; 
following the planned IA, subjects received 50 mg IMR-687 or placebo for 4 weeks, and if well 
tolerated, escalated from 50 mg to 100 mg for the remaining 20 weeks of the study. 
A total of 93 subjects with SCD were enrolled, randomized, and received study drug (IMR-687 
or placebo) in Study IMR-SCD-102 (58 subjects in Populations A/A1 and 35 subjects in 
Populations B/B1; 63 subjects received IMR-687 and 30 subjects received placebo). In summary, 
qd dosing of IMR-687 was generally safe and well tolerated. Additional information on the study 
results is provided in the Investigator’s Brochure (IB). 


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5. 
RATIONALE 
5.1. 
Study Rationale and IMR-687 Dose Rationale 
This is a phase 2b, randomized, double-blind, placebo-controlled, multicenter study of subjects 
aged 18 to 65 years with SCD (HbSS, HbSβ0 thalassemia, or HbSβ+ thalassemia) to evaluate the 
safety and efficacy of the PDE9 inhibitor, IMR-687, administered qd for 52 weeks. Overall, this 
study will provide data on IMR-687 doses of ≥3.0 to ≤6.7 mg/kg (200 to 400 mg). 
In a relevant model of anemia (Hbbth1/th1 mice), oral administration of IMR-687 for 30 days at 
30 mg/kg/day (human equivalent dose [HED] of 2.4 mg/kg/day) or 60 mg/kg/day (HED of 
4.9 mg/kg/day) increased RBCs and Hb, and reduced reticulocytes. The degree of these changes 
was dose dependent, with statistically significant improvement at the higher dose of 60 mg/kg. In 
addition, IMR-687 at 60 mg/kg improved erythroblast differentiation, suggesting a role for this 
compound in the improvement of ineffective erythropoiesis, a problem in a number of Hb 
disorders. 
Clinical safety and tolerability data are available from Study IMR-SCD-101 in healthy 
volunteers for IMR-687 administered at doses up to 6 mg/kg/day in the fasted SAD portion 
(Part A) and at doses up to 4.5 mg/kg/day for 7 days in the fed MAD portion (Part C), as well as 
from the completed phase 2a study in fed SCD subjects (IMR-SCD-102). Based on these data, a 
dose range from 3 mg/kg to approximately 6 mg/kg is expected to be tolerable, especially if 
taken with food because administration with food appears to reduce both the incidence and 
severity of GI-related TEAEs, such as nausea and/or upper GI pain. The onset of nausea in the 
healthy volunteer study was rapid (between 30 to 120 minutes), generally lasted 2 to 8 hours, and 
was mild in nature at doses ≤4.5 mg/kg (lower dose). These potential AEs of nausea, upper GI 
pain, and emesis are easily monitorable and are self-limited if dosing is stopped.  
Furthermore, following qd dosing for 7 days in fed healthy volunteers, exposure (AUC) in 
healthy volunteers increased in a near dose-proportional manner (a 4.1-fold increase for a 
4.5-fold change in dose [see Section 4.2.3.1]). For the higher dose arm of up to 6.7 mg/kg 
(assumed to be equivalent to approximately a 400 mg dose), the predicted Day 1 exposure is 
32.0 µg•h/mL, which is approximately 2.7-fold below the Week 39 exposure (AUC from time 0 
to 24 hours [AUC0-24]) in the female dog (most conservative species/gender). PK plotting 
(e.g., mean trough concentrations at 24 hours after study drug administration [C24]) predicted that 
higher exposure to IMR-687 should result in drug levels above the estimated concentration at 
which inhibition is 90% (IC90) for approximately 22 hours at a 300-mg dose and approximately 
24 hours at a 400-mg dose. This possible IC90 advantage with respect to inhibition of the target, 
PDE9, further supports evaluating both the lower and higher doses of IMR-687 and specifically 
doses of up to 6.7 mg/kg, which can provide adequate target coverage to potentially improve 
clinical benefit. 
This study initially imposed a minimum allowable body weight for enrollment of 45 kg and a 
67-kg body weight gate for the administered tablet strength to ensure that subjects in the lower 
dose IMR-687 group received a dose equating to no more than the 4.5 mg/kg evaluated in the 
MAD part of the healthy volunteer study. Subsequently, the Data Monitoring Committee (DMC) 
approved the opening of enrollment in the higher dose IMR-687 group (up to 6.7 mg/kg). Having 
established safety and tolerability of the lower dose(s), the DMC also approved a change in body 


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weight gate to 60 kg and the resultant modified dose range of up to 5.0 mg/kg in the lower dose 
group (with the minimum weight threshold of 45 kg unchanged). Starting from Protocol Version 
4.0, subjects in the IMR-687 lower dose group will receive ≥3.4 to ≤5.0 mg/kg and subjects in 
the higher dose group will receive >5.0 to ≤6.7 mg/kg; no subject will receive more than 
6.7 mg/kg. Under Protocol Version 3.0, the dose ranges were ≥3.0 to ≤4.5 mg/kg in the lower 
dose group and >4.5 to ≤6.7 mg/kg in the higher dose group. Therefore, the overall dose range 
during the course of the study is ≥3.0 to ≤6.7 mg/kg. 
5.2. 
Benefit/Risk Assessment 
IMR-687 is currently being investigated for the treatment of SCD as its primary indication. It is 
anticipated that IMR-687, when compared to established therapy (i.e., HU), will maintain a 
similar or improved efficacy profile while potentially having a better safety profile, without the 
side effects that limit the use of HU (e.g., myelosuppression and mutagenicity/carcinogenicity 
risk) or the need for close monitoring and dose adjustments to balance benefit and risk.  
Consequently, the frequent monitoring of blood counts required for patients who use HU would 
not be required for IMR-687. The proposed dosing in this study is between ≥3.4 to ≤6.7 mg/kg 
daily; the resultant exposures are anticipated to be in the pharmacologically active range based 
on available nonclinical and clinical data (see Section 5.1 for dose selection rationale). Based on 
the observed safety and tolerability of IMR-687 in the first-in-human study (Section 4.2.3.1) and 
subsequent phase 2a study in SCD subjects, these dose levels should be tolerable and may have a 
clinically beneficial PD effect in subjects with SCD.  
Based on the data from healthy volunteers and SCD subjects to date, IMR-687 is considered to 
be safe and well tolerated, with the most common side effects being sickle cell anemia with 
crisis, abdominal pain, nausea, headache, indigestion, diarrhea/loose stools, and influenza-like 
illness, which are mild and easily managed. Newly emerging safety data will be updated in the 
IB and informed consent form (ICF). The potential benefits and risks are summarized below. 
5.2.1. 
Potential Benefits 
Potential benefits include the production of increased levels of HbF, which is associated with 
decreased RBC sickling and improved blood flow, and decreases in biomarkers of adhesion and 
inflammation; individually and together, these PD changes may lead to fewer painful 
SCD-associated crises. 
5.2.2. 
Potential Risks 
The potential risks of IMR-687 are inferred from the relevant nonclinical findings as well as the 
results of the first-in-human study in healthy volunteers (IMR-SCD-101) and the results of the 
phase 2a study in subjects with SCD (IMR-SCD-102). These potential risks are briefly 
summarized in the sections below. Further details are provided in the IB. 
5.2.2.1. 
Gastrointestinal 
Based on the observed incidence of nausea in healthy volunteers in the first-in-human study, oral 
administration of IMR-687 may result in nausea within the first several hours of dosing. Nausea 
observed thus far was transient and self-limited. A dose-limiting toxicity of emesis occurred at 
6 mg/kg when IMR-687 was administered in the fasted state. Oral administration of study drug 


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with food significantly reduced the incidence and severity of the nausea TEAE. No correlated 
changes in liver function tests were observed in any healthy volunteers administered IMR-687, 
or specifically in those subjects with nausea, with or without emesis. 
5.2.2.2. 
Central Nervous System 
Mild headaches (self-limited or treatable with acetaminophen) were observed in the 
first-in-human study in healthy normal volunteers and appeared to occur with nausea. Headaches 
were also observed in the phase 2a study. Oral administration of study drug with food 
significantly reduced the incidence and severity of the headache TEAE. 
5.2.2.3. 
Cardiovascular 
In nonclinical safety pharmacology and 14-day GLP toxicology studies in beagle dogs, IMR-687 
appeared to result in increases in heart rate that did not appear to be dose-dependent. In the safety 
pharmacology study in dogs, at doses of 75 mg/kg, statistically significant changes in heart rates 
were observed. In the 14-day toxicology study in dogs, the highest heart rates were noted at the 
highest dose level of 75 mg/kg but did not reach statistical significance. In a subsequent 9-month 
study in dogs at doses up to and including 50 mg/kg/day, there was no evidence of any increases 
in heart rate and there were no histopathological abnormalities noted in cardiac tissue. In healthy 
volunteers in the first-in-human study, at doses between 0.3 and 6 mg/kg, sporadic observations 
of sinus tachycardia (i.e., heart rates >100 bpm) occurred in various subjects, including a subject 
in the MAD on placebo. The contribution of concomitant AEs such as headache to the rise in 
heart rate could not be excluded. No dose dependency or dose-duration dependency was noted 
for these heart rate observations. No signs of prolongation of corrected QT interval, Fridericia’s 
formula (QTcF) were noted in any cohort of healthy volunteers at any dose of IMR-687.  
In the safety analysis of Study IMR-SCD-102, with respect to vital signs, there were no changes 
in systolic or diastolic blood pressure and pulse, and there were no changes in respiratory rate. In 
the IMR-SCD-102 clinical study, the mean interim steady-state AUC0-24 was 16,300 ng•hr/mL 
for the 200 mg (~2.9 mg/kg) IMR-687 dose level. In the 39-week dog toxicology study 
mentioned above, mean AUC0-24 was ≥87,500 ng•hr/mL at the NOAEL in female dogs, resulting 
in safety margins of at least ~5.3-fold for the 200 mg clinical dose. With dosing in the current 
study being up to 400 mg (≤6.7 mg/kg), safety margins of at least 2.7-fold are maintained. 
Monitoring of vital signs is recommended for subjects in IMR-687 studies. In the event of noted 
persistent and/or clinically significant tachycardia, other causes of tachycardia, particularly pain 
and dehydration, should also be considered. 
5.2.3. 
Potential Interactions 
In vitro studies indicate that IMR-687 is not expected to competitively inhibit the major human 
CYP enzymes, including CYPs 3A4, 2D6, 2C9, 2C19, 2C8, 1A2, and 2B6. IMR-687 does have 
the potential for induction of CYP3A4/5 (in vitro EC50 = 32.4 to 133 µM) and other drug 
metabolizing enzymes whose expression levels are also controlled by the pregnane X receptor 
(PXR). In addition, IMR-687 has been shown to primarily be a CYP3A4 substrate 
(Km  127 µM); IMR-687 may be at least partially cleared as unchanged drug. 
After oral administration, concentrations of IMR-687 in this study may reach sufficient exposure 
in the gastric mucosa and/or the liver (during absorption) to induce (upregulate) CYP3A4 and/or 


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CYP3A5 protein expression in these organs. Induced expression levels of CYP3A4 and CYP3A5 
may not return to baseline levels until after discontinuation of IMR-687 dosing, which is likely to 
require approximately 1 week of washout due to the CYP3A protein half-life. Consequently, if a 
subject in this study is started on a medication that is primarily metabolized (and cleared) by 
CYP3A4/5, the subject should be followed appropriately to determine if the exposure to the 
concomitant medication is maintained at levels sufficient for efficacy. For example, if a subject 
is started on oxycodone for pain management or ondansetron for nausea, symptom resolution 
should be followed to determine if higher doses of either medication are required to reach target 
outcomes, as co-administration of IMR-687 may result in a reduction in the overall exposure to 
oxycodone or ondansetron. 
In addition, because IMR-687 is expected to be at least partially cleared by CYP3A4-mediated 
metabolism, a drug interaction could also result from co-administration of other concomitant 
medications that at least partially (or solely) rely on CYP3A4-mediated metabolism for their in 
vivo clearance. The underlying mechanism for this would be in vivo competition for CYP3A4 
metabolism in the gastric mucosa and/or the liver. In this case, exposure increases in IMR-687 
and/or the CYP3A-dependent concomitant drug(s) may occur. CYP3A competition could also 
result in exposure changes for active circulating metabolites that contribute to the overall 
efficacy. Finally, co-administration of moderate to strong CYP3A selective inhibitors, such as 
ketoconazole, should be avoided as this may increase the exposure of IMR-687. 
As IMR-687 is also a substrate of P-gp (Km > 500 µM) as well as a substrate of BCRP 
(Km = 44.5 µM) and an inhibitor of BCRP (IC50 = 32.5 µM), co-administration of substrates or 
inhibitors of P-gp and BCRP should also proceed with caution.  
See the Appendix 1 references for a list of in vivo CYP3A-sensitive substrates, inhibitors of 
CYP3A probe substrates, and inducers of CYP3A probe substrates; a list of in vivo inhibitors of 
P-gp probe substrates; and a list of in vivo inducers of CYP3A probe substrates from published 
drug interactions. Currently there are no such listings for BCRP. 
Analysis of IMR-SCD-102 data found that 100 mg IMR-687 dosed qd had no notable impact on 
HU exposure for daily HU doses ranging from 500 to 2000 mg. In addition, PK was comparable 
for IMR-687 when administered as monotherapy or in combination with HU, implying no 
notable impact of HU on IMR-687 exposure. 
The anti-platelet and anti-coagulant drugs with a high potential for a clinically relevant drug-
drug interaction (DDI) include direct acting oral anti-coagulants (DOACs) apixaban, dabigatran, 
rivaroxaban, edoxaban, and ticagrelor, as well as the Vitamin K antagonist warfarin, based on 
published clinical drug interaction studies. 
If there is any question as to whether a substance is permitted, please consult the medical 
monitor and/or sponsor.  
See also Section 9.6.2 on prohibited concomitant medications/therapies. 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
6.1.1. 
Primary Efficacy Objective 
 To evaluate the effect of IMR-687 versus placebo on the annualized rate of vaso-
occlusive crises (VOCs) 
6.1.2. 
Primary Safety Objective 
 To evaluate the safety and tolerability of IMR-687 versus placebo 
6.1.3. 
Key Secondary Efficacy Objectives 
 To evaluate the effect of IMR-687 versus placebo on the time to the first occurrence 
of a VOC 
 To evaluate the fetal hemoglobin (HbF) response to IMR-687 versus placebo 
6.1.4. 
Other Secondary Efficacy Objectives 
 To evaluate the effect of IMR-687 versus placebo on other measures of VOCs 
 To evaluate the effect of IMR-687 versus placebo on percentage of cells positive for 
HbF (% F-cells) and total Hb 
 To evaluate the effect of IMR-687 versus placebo on biomarkers of RBC hemolysis 
 To evaluate the effect of IMR-687 versus placebo on quality of life (QoL) measures 
 To evaluate the effect of IMR-687 versus placebo on biomarkers of adhesion, 
inflammation, and cardiac stress and on RBC indices 
6.1.5. 
Secondary Pharmacokinetic Objective 
 To evaluate the PK exposure of IMR-687 
6.1.6. 
Exploratory Objective 
 To evaluate the effect of IMR-687 versus placebo on renal function 
6.2. 
Endpoints 
6.2.1. 
Primary Efficacy Endpoint 
 Annualized rate of VOCs  
VOC is defined as a documented episode of an acute painful crisis (for which there 
was not an explanation other than VOC) that involves moderate to severe pain lasting 
for at least 2 hours and at least one of the following: 
 Use of escalated analgesia (including healthcare professional-instructed use of an 
analgesic prescription) 


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 A hospital, emergency department, or clinic visit and/or healthcare telephone 
consultation at the time of occurrence 
 Diagnosis of ACS (defined as an acute illness characterized by fever and/or 
respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray), 
hepatic sequestration, splenic sequestration, or priapism (in males) 
6.2.2. 
Safety Endpoints 
 AEs, serious adverse events (SAEs), clinically significant changes in laboratory tests, 
clinically significant changes in vital signs, and clinically significant changes in 
ECGs 
6.2.3. 
Key Secondary Efficacy Endpoints 
 Time to first VOC 
 Proportion of HbF responders (defined as the proportion of subjects with an absolute 
increase of ≥3% in HbF from baseline) at Week 24 
6.2.4. 
Other Secondary Efficacy Endpoints 
Other secondary endpoints that will be tested include the following: 
 Proportion of VOC-free subjects 
 Annualized rate of hospitalizations for VOCs 
 Time to second VOC 
 Proportion of HbF responders (defined as the proportion of subjects with an absolute 
increase of ≥3% in HbF from baseline) at Week 52 
 Change from baseline in HbF (%) and F-cells (%) at Week 24 and Week 52 
 Proportion of Hb responders (defined as the proportion of subjects with an increase of 
≥1.0 g/dL in total Hb from baseline) at Week 24 and Week 52 
 Change from baseline in total Hb (g/dL) at Week 24 and Week 52 
 Change from baseline in biomarkers of RBC hemolysis (% and absolute reticulocytes, 
unconjugated [indirect] bilirubin, and lactate dehydrogenase [LDH]) at Week 24 and 
Week 52 
 Change from baseline in each measured subdomain of the Adult Sickle Cell Quality 
of Life Measurement Information System (ASCQ-Me®) questionnaire at Week 24 
and Week 52 
 Change from baseline in total preference score and individual domain scores of the 
Patient-Reported Outcomes Measurements Information System – Preference 
(PROMIS® 29 + 2 Profile v2.1 [PROPr]) questionnaire at Week 24 and Week 52 
 Change from baseline in overall score of the Sickle Cell Self-Efficacy Scale (SCSES) 
at Week 24 and Week 52 


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 Change from baseline in biomarkers of adhesion such as soluble E-selectin (E-sel), 
P-selectin (P-sel), intercellular adhesion molecule 1 (ICAM-1), and vascular cell 
adhesion molecule 1 (VCAM-1) at Week 24 and Week 52 
 Change from baseline in biomarkers of inflammation such as high-sensitivity 
C-reactive protein (hsCRP) and myeloperoxidase (MPO) at Week 24 and Week 52 
 Change from baseline in biomarkers of cardiac stress such as N-terminal prohormone 
of brain natriuretic peptide (NT-proBNP) at Week 24 and Week 52 
 Change from baseline in RBC indices, such as mean corpuscular volume (MCV), at 
Week 24 and Week 52 
6.2.5. 
Secondary Pharmacokinetic Endpoint 
 PK profile (concentration-time measurements) and population PK of IMR-687 
6.2.6. 
Exploratory Endpoint 
 Change from baseline in renal function as measured by the urine protein-to-creatinine 
(Pr:Cr) ratio and microalbumin at Week 24 and Week 52 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a phase 2b, randomized, double-blind, placebo-controlled, multicenter study of subjects 
aged 18 to 65 years with SCD (HbSS, HbSβ0 thalassemia, or HbSβ+ thalassemia) to evaluate the 
safety and efficacy of the PDE9 inhibitor, IMR-687, administered qd for 52 weeks. This study 
will enroll approximately 99 subjects with SCD. This study consists of a screening period (up to 
4 weeks), a double-blind treatment period (52 weeks), and a safety follow-up period (4 weeks). 
The study schematic is provided in Figure 1, and the schedule of assessments is provided in 
Table 1. 
7.1.1. 
Screening 
After providing informed consent and signing the ICF, subjects will enter an up to 28-day 
screening period. The following information will be obtained, and procedures will be performed 
for all potential subjects at the screening visit: medical/disease history, vital signs, ECG, 
complete PE, laboratory tests (including safety, specialty hematology, and PD assessments). For 
a complete list of screening procedures, refer to the schedule of assessments (Table 1) and 
Section 11. 
All screening procedures will be completed within 28 days before randomization. In some cases, 
there may be subjects who are eligible for the study but fall outside of the 28-day screening 
window. In these specific cases, the medical monitor may use his/her clinical judgment and 
allow a patient to be randomized without full re-screening in order to prevent having the subject 
undergo additional screening assessments unduly, provided that the patient’s safety is not at risk 
and the integrity of the study will not be compromised. The medical monitor will be explicit as to 
which screening assessments must be repeated, if any, and will clearly document all decisions. 
If a subject is considered a screen failure, he/she may be rescreened once with sponsor approval. 
If the investigator would like to repeat a screening assessment, such as chemistry laboratory 
testing, more than once, prior approval by the medical monitor is required. 
7.1.2. 
Treatment Period 
Subjects will receive either IMR-687 (lower dose [≥3.4 to ≤5.0 mg/kg; administered as either 
200 or 300 mg] or higher dose [>5.0 to ≤6.7 mg/kg; administered as either 300 or 400 mg]) or 
placebo in a blinded fashion. Initially, subjects will be randomly assigned in a 2:1 ratio to receive 
either IMR-687 lower dose or placebo. Prior to the introduction of IMR-687 higher dose, the 
DMC will review safety data for at least 5 subjects who received IMR-687. If the DMC 
recommends inclusion of the higher dose, randomization will then proceed in a 1:2:1 ratio 
(IMR-687 lower dose, IMR-687 higher dose, or placebo). During study conduct under Protocol 
Version 3.0, the DMC approved the opening of enrollment in the higher dose IMR-687 group, 
which went into effect on 12 March 2021. 
Subjects may or may not be concomitantly receiving a stable dose of HU according to the 
subject’s established treatment plan. Randomization will be stratified by use of HU and by 
region. 


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Subjects will return to the investigational site at Week 1 for a safety assessment, and qualified 
site personnel will contact the subject by telephone at Week 2 and Week 6 to capture potential 
AEs and concomitant medications. 
Subjects will be seen at the investigational site approximately every 4 weeks through Week 24, 
then every 6 weeks through Week 36, and then every 8 weeks through Week 52 (end of 
treatment [EOT]), with a safety follow-up visit at Week 56 (end of study [EOS]). Safety will be 
monitored throughout the study, and PK, PD, QoL, and clinical outcome measures will be 
performed at the visits shown in the schedule of assessments for (Table 1). QoL assessments 
include ASCQ-Me®, PROPr, and SCSES. 
7.1.3. 
Open-Label Extension 
Subjects who complete treatment (Week 52) in this study may be eligible to enroll in a planned 
open-label extension (OLE) study The EOS safety follow-up visit (Week 56) will not be 
expected for subjects who directly roll over to the OLE study. 


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Figure 1: 
Study Design 
 
Abbreviation: DMC = data monitoring committee. 
* Prior to the introduction of IMR-687 higher dose, the DMC will review safety data for at least 5 subjects who received IMR-687. If the DMC recommends inclusion of the higher 
dose, randomization across 3 dose groups will then proceed as shown.  
During study conduct under Protocol Version 3.0, the DMC approved the opening of enrollment in the higher dose IMR-687 group, which went into effect on 12 March 2021. 


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Table 1: 
Schedule of Assessments 
Screening 
Period 
Baseline 
Treatment Period 
Follow-up 
Period 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Study Week 
-4 to 0 
NA 
1 
2 
4 
6 
8 
12 
16 
20 
24 
30 
36 
44 
ET/EOT 
52p 
EOS 
56 
Study Day 
-28 to -1 
1a 
7  
± 2 
14  
± 3 
28  
± 5 
42  
± 5 
56  
± 5 
84  
± 5 
112  
±7 
140  
± 7 
168  
± 7 
210  
± 7 
252  
± 7 
308  
± 7 
364  
± 7 
392 
± 7 
Administrative Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/disease history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteriab 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone visitsc 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Vital signsd 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical examinatione 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and serum chemistry 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation studies 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
Urinalysis with urine creatinine, Pr:Cr 
ratio, and microalbumin 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Table 1: 
Schedule of Assessments (Continued) 
Screening 
Period 
Baseline 
Treatment Period 
Follow-up 
Period 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Study Week 
-4 to 0 
NA 
1 
2 
4 
6 
8 
12 
16 
20 
24 
30 
36 
44 
ET/EOT 
52p 
EOS 
56 
Study Day 
-28 to -1 
1a 
7  
± 2 
14  
± 3 
28  
± 5 
42  
± 5 
56  
± 5 
84  
± 5 
112  
±7 
140  
± 7 
168  
± 7 
210  
± 7 
252  
± 7 
308  
± 7 
364  
± 7 
392 
± 7 
Serum pregnancy testg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testg 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
Clinically indicated virologyh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventsi 
Continuous 
Concomitant medicationsi 
Continuous 
Efficacy and Pharmacodynamic Assessments 
Specialty hematologyj 
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
PD biomarkersk 
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
QoL toolsl  
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
CV marker 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
X  
 
X 
 
Pharmacokinetic Assessments 
IMR-687 plasma PK samplingm 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Study Drug Procedures 
Study drug dispensing 
 
X 
 
 
X 
 
X 
X 
X 
X 
Xn 
Xn 
Xn 
Xn 
 
 
Study drug administrationo 
 
Oral administration IMR-687 or matching placebo qd 
 


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Table 1 
Schedule of Assessments (Continued) 
Abbreviations: AE = adverse event; ASCQ-Me = Adult Sickle Cell Quality of Life Measurement Information System; BP = blood pressure; CV = cardiovascular; 
ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; ET = early termination; F-cells = cells positive for HbF; HbF = fetal hemoglobin; HBsAg = hepatitis B 
surface antigen; HCV = hepatitis C virus; HR = heart rate; HU = hydroxyurea; ICAM-1 = intercellular adhesion molecule 1; IgM = immunoglobulin M; 
MPO = myeloperoxidase; NA = not applicable; PD = pharmacodynamic; PE = physical examination; PK = pharmacokinetics; Pr:Cr = protein-to-creatinine (ratio); 
PROPr = Patient-Reported Outcomes Measurements Information System – Preference; qd = once daily; QoL = quality of life; SCSES = Sickle Cell Self-Efficacy Scale; 
TEAE = treatment-emergent adverse event; VCAM-1 = vascular cell adhesion molecule 1. 
Note: Unscheduled visits may occur, limited to visits resulting from potential TEAEs, drug dispensation, or other urgent study-related procedures. 
a Day 1 assessments should be performed prior to study drug administration. 
b All inclusion and exclusion criteria will be assessed at the Screening Visit; continued eligibility based on these criteria will be confirmed on Day 1. 
c Qualified site personnel will contact the subject at Week 2 and Week 6 to capture potential TEAEs and concomitant medications. Subjects will also be reminded of compliance 
with drug and the next visit schedule. If any AEs of significant clinical concern are identified during the telephonic visit, the subject will be requested to come into the site to be 
assessed. 
d Vital signs include HR, respiratory rate, BP, and body temperature and should be consistently measured in either the sitting or semi-supine position. At the Day 1 and Week 4 
visits, vital signs will be taken pre-dose and 2 hours (±20 minutes) post-dose, during the PK assessments. At all other timepoints, vital signs can be taken irrespective of taking 
study drug. 
e Complete PEs will be performed at Screening and at Weeks 12, 24, 36, 52, and 56; these consist of a general examination of the body, including the abdomen, heart, lungs, 
lymph nodes, back/neck, neurological system, skin, extremities, head, eyes, nose, and throat. At all other visits, symptom-directed PEs will be obtained after identification of 
AEs deemed by the investigator to be of significant clinical concern. 
f All ECGs to be performed in triplicate. At the Baseline, Week 1, and Week 4 visits, ECGs will be obtained pre-dose and 2 hours (±30 minutes) post-dose. At all other 
timepoints, ECG will be taken pre-dose. 
g Females of childbearing potential only. A serum pregnancy test will be performed during screening via a central laboratory. All subsequent pregnancy tests will be urine 
pregnancy tests performed locally (with test kits provided by the central laboratory). If a urine pregnancy test is positive, the result must be confirmed with a serum pregnancy 
test. 
h Serum virology (screening assessment) will be conducted only if clinically indicated. Testing will be performed through a central laboratory and may include HBsAg, hepatitis A 
IgM, and HCV antibody.  
i AEs and concomitant medications, including opioids and HU use, will be recorded at each visit throughout the study from screening through the EOS (Week 56) follow-up. 
j Includes HbF and % F-cells. Blood samples should be obtained prior to administration of study drug. 
k PD biomarkers that are not already assessed as part of standard hematology or serum chemistry testing may include, but are not limited to, the following: soluble E-selectin, 
P-selectin, ICAM-1, VCAM-1, and MPO. 
l QoL assessments include the specified components of the ASCQ-Me®, PROPr, SCSES. Refer to Section 11.2.4. The translated QoL assessments from PROPr will be used when 
available. 
m At the Day 1 and Week 4 visits, serial blood samples for IMR-687 (including metabolites and HU, if applicable) plasma concentrations will be drawn pre-dose (within 
30 minutes) and at 15 minutes (±5 minutes), 30 minutes (±5 minutes), and 3 hours (±20 minutes) after administration of study drug. A trough blood sample will be drawn 
pre-dose at Week 24 and on the last day of dosing (Week 52). The date/time of the last administered dose will be recorded. 
n Each study drug bottle will contain 84 tablets. The indicated visits will require 2 bottles to be dispensed. 
o On days when study drug is taken in the clinic, food details will also be recorded. 
P The EOS (Week 56 follow-up) visit will not be expected for subjects who directly roll over to the OLE study. Refer to Section 7.1.3. 
 


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7.2. 
Data Monitoring Committee 
The specific activities of the DMC will be governed by a charter that will define the DMC’s 
membership, meeting frequency, procedures/conduct, and requirements for reporting its 
observations and recommendations to the sponsor. 
To ensure safety oversight throughout the study, a DMC will review safety and preliminary 
efficacy data and provide recommendations to the sponsor as described below. 
The DMC will convene at the following times and for the following activities during the study:  
 Review safety data for at least 5 subjects who received IMR-687 at the lower dose 
and make recommendation as to the inclusion of the higher dose. 
 Review safety data to confirm acceptable safety and tolerability of the higher dose of 
IMR-687 and make recommendation as to whether the dose levels could be modified. 
 Review safety data on a periodic basis as defined in the DMC charter. For example, 
results of blinded laboratory tests will be communicated to the investigator if a 
subject’s absolute reticulocyte count declines to <80 × 108/L, Hb declines to 
<5.0 g/dL, or Hb declines to ≥3 g/dL from baseline (Day 1) (but this does not require 
breaking of the treatment assignment blind). This is to ensure subject safety by 
allowing the investigator to monitor relevant safety data. 
 At any time during the study – upon request by the sponsor, medical monitor, or 
DMC – should a concern arise from emerging safety data for which DMC review and 
assessment is desired. This includes the emergence of a frequency or pattern of AEs 
or SAEs that suggest an unexpected or otherwise concerning safety signal. At any 
time, the DMC may recommend to stop a dose arm or the study. 
The DMC may review the following subject data, depending on the scope of the meeting, and 
may recommend to continue the study as planned, modify the study, or terminate the study for 
safety concerns: 
 Unblinded safety, PK, and preliminary efficacy/PD data, which may include TEAEs, 
SAEs, PK data, clinical laboratory test results, vital signs, and other relevant data for 
all subjects randomized. 
 Additionally, the DMC chairperson will receive copies of all SAE reports for ongoing 
review during the study. The DMC chairperson may forward the SAE reports to the 
full DMC if he/she feels that their immediate input on, or awareness of, the SAE 
would be helpful. 
All assessments, decisions, and recommendations by the DMC will be documented in writing as 
noted in the DMC charter and prior to any resultant changes to the study unless their immediate 
implementation is considered necessary for subject safety. The composition of the DMC will be 
detailed in the DMC charter. 
7.3. 
Number of Subjects 
A total of up to approximately 99 adult subjects are expected to enroll in this study. 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Each subject must meet all the following criteria to be enrolled in the study:  
1. Male or female aged ≥18 to ≤65 years at the time of ICF signing. 
2. Confirmed diagnosis of SCD (HbSS, HbSβ0 thalassemia, or HbSβ+ thalassemia) in 
the medical record; if not available, the diagnosis must be confirmed at the site’s local 
laboratory instead. 
3. Subjects must have had at least 2 and no more than 12 documented episodes of VOC 
in the past 12 months at the time of ICF signing and at randomization (Day 1). 
For study eligibility, VOC is defined as a documented episode of an acute painful 
crisis (for which there was not an explanation other than VOC) that involved 
moderate to severe pain lasting for at least 2 hours and at least one of the following: 
 Use of escalated analgesia (including healthcare professional-instructed use of an 
analgesic prescription) 
 A hospital, emergency department, or clinic visit and/or healthcare telephone 
consultation at the time of occurrence 
 Diagnosis of ACS (defined as an acute illness characterized by fever and/or 
respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest 
X-ray), hepatic sequestration, splenic sequestration, or priapism (in males) 
4. Hb of >5.5 and <10.5 g/dL; Hb values within 21 days post-transfusion will be 
excluded. 
5. This inclusion criterion has been removed. 
6. Subjects receiving HU must have received it continuously for at least 6 months prior 
to signing the ICF, and must have been on a stable dose for at least 3 months prior to 
signing the ICF, with no anticipated need for dose adjustments during the study 
including the screening period, in the opinion of the investigator. 
7. Female subjects must not be pregnant or breastfeeding and be highly unlikely to 
become pregnant. Male subjects must be unlikely to impregnate a partner. Male or 
female subjects must meet at least one of the following criteria: 
 A female subject who is not of reproductive potential is eligible without requiring 
the use of contraception. A female subject who is not of reproductive potential is 
defined as one who: (1) has reached natural menopause (defined as 12 months of 
spontaneous amenorrhea without an alternative medical cause, and can be 
confirmed with serum follicle-stimulating hormone [FSH] levels in the 
postmenopausal range as determined by the central laboratory); (2) is 6 weeks 
postsurgical bilateral oophorectomy with or without hysterectomy; or (3) has 
undergone bilateral tubal ligation. Spontaneous amenorrhea does not include 


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cases for which there is an underlying disease that causes amenorrhea 
(e.g., anorexia nervosa). 
 A female of reproductive potential must have 2 negative pregnancy tests as 
verified by the investigator prior to starting study therapy. She must agree to 
ongoing pregnancy testing during the course of the study, at the EOT visit, and at 
the EOS visit. This applies even if the subject practices true abstinence from 
heterosexual contact. 
 A male subject who is not of reproductive potential is eligible without requiring 
the use of contraception. A male subject who is not of reproductive potential is 
defined as one who has undergone a successful vasectomy. A successful 
vasectomy is defined as (1) microscopic documentation of azoospermia or 
(2) a vasectomy more than 2 years ago with no resultant pregnancy despite sexual 
activity post-vasectomy. 
 A male or female subject who is of reproductive potential agrees to remain truly 
abstinent or use (or have their partner use) acceptable methods of highly effective 
contraception starting from the time of consent through 3 months after the 
completion of study drug. True abstinence is defined as abstinence that is in line 
with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of the study, and withdrawal are not acceptable 
methods of contraception. Acceptable methods of highly effective birth control 
are combined or progesterone-only hormonal contraception that is associated with 
inhibition of ovulation, intrauterine device, and intrauterine hormone-releasing 
system.  
8. Be capable of giving informed consent and reading and signing the ICF after the 
nature of the study has been fully explained by the investigator or investigator 
designee. 
9. Be willing and able to complete all study assessments and procedures and to 
communicate effectively with the investigator and site staff. 
8.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Hospital discharge for sickle cell crisis or other vaso-occlusive event within the 
4 days prior to randomization (Day 1). 
2. Subjects participating in a chronic/prophylactic RBC transfusion program 
(i.e., regularly scheduled RBC transfusions); any transfusions within 21 days of 
screening or baseline Hb measurements. 
3. Subjects with HbF >25% at screening. 
4. Subjects with known active hepatitis A, hepatitis B, or hepatitis C, with active or 
acute event of malaria, or who are known to be positive for human immunodeficiency 
virus (HIV). 


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5. For female subjects of childbearing potential, a positive serum human chorionic 
gonadotropin (hCG) test (screening) or a positive urine hCG test at randomization 
(Day 1). 
6. Significant kidney disease as indicated by, for example, estimated glomerular 
filtration rate (eGFR) <45 mL/min as calculated by the equation from the 
Modification of Diet in Renal Disease (MDRD) Study using creatinine, age, sex, and 
ethnicity (modified MDRD formula). 
7. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3× the upper 
limit of normal. 
8. Body mass index (BMI) <17.0 kg/m2 or >35 kg/m2; or total body weight <45 kg. 
9. Current or history of malignancies (solid tumors and hematological malignancies), 
unless the subject has been free of the disease (including completion of any active or 
adjuvant treatment for prior malignancy) for ≥5 years. However, subjects with the 
following history of/concurrent conditions are allowed if, in the opinion of the 
investigator, the condition has been adequately diagnosed and is determined to be 
clinically in remission, and the subject’s participation in the study would not 
represent a safety concern: 
a. Basal or squamous cell carcinoma of the skin 
b. Carcinoma in situ of the cervix 
c. Carcinoma in situ of the breast 
d. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, 
nodes, metastasis clinical staging system) 
10. History of a clinically significant allergic reaction or hypersensitivity, as judged by 
the investigator, to any drug or any component of the study drug formulations used in 
the study (see the IB). 
11. History of unstable or deteriorating cardiac or pulmonary disease within 6 months 
before signing the ICF, including but not limited to the following:  
a. Unstable angina pectoris or myocardial infarction or elective coronary 
intervention 
b. Congestive heart failure requiring hospitalization 
c. Uncontrolled clinically significant arrhythmias 
12. Any condition affecting drug absorption, such as major surgery involving the stomach 
or small intestine (prior cholecystectomy is acceptable). 
13. On ECG testing at ICF signing and/or randomization (Day 1), a QTcF >450 ms in 
men and >470 ms in women on 2 or more of the triplicate ECGs, or the presence of 
clinically significant ECG abnormalities as determined by the investigator. 
14. Major surgery within 8 weeks or minor surgery within 2 weeks of randomization 
(Day 1). 


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15. Stroke requiring medical intervention within 24 weeks prior to randomization 
(Day 1). 
16. Subjects taking DOACs (apixaban, dabigatran, rivaroxaban, edoxaban, or ticagrelor) 
or taking warfarin, unless they stopped the treatment at least 28 days prior to 
randomization (Day 1); low molecular weight heparins are allowed in the 
peri-operative period; aspirin use (<100 mg per day) is allowed before and during the 
study. 
17. Poorly controlled diabetes mellitus in the opinion of the investigator, for example 
1) Hb A1c >9.0% within 12 weeks prior to randomization (in the medical history); 
2) short-term hyperglycemia leading to hyperosmolar or ketoacidotic crisis; and/or 
3) history of diabetic cardiovascular complications. 
18. Subject has received chronic systemic glucocorticoids within 12 weeks prior to 
randomization (≥5 mg/day prednisone or equivalent). Physiologic replacement 
therapy for adrenal insufficiency is allowed. 
19. Any clinically significant bacterial, fungal, parasitic, or viral infection requiring 
antibiotic therapy should delay screening/randomization (Day 1) until the course of 
antibiotic therapy has been completed. This includes, but is not limited to, long-term 
tuberculosis treatment. 
20. Participated in another clinical study of an investigational agent (or medical device) 
within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is 
currently participating in another study of an investigational agent (or medical 
device).  
21. Prior exposure to IMR-687. 
22. History of crizanlizumab (Adakveo®) or voxelotor (Oxbryta®) use within 6 months 
prior to signing the ICF or anticipated need for such agents during the study. 
23. Consumption/use of the following drugs or other substances within the specified time 
periods before randomization or plans to consume/use at any time during the study. If 
there is any question as to whether a substance is permitted, please review the product 
labeling (if applicable) and consult the medical monitor and/or sponsor. 
a. Phosphodiesterase type 5 (PDE5) inhibitors (including but not limited to 
sildenafil, tadalafil, and vardenafil) within 7 days prior to randomization (Day 1) 
or plans to use during the study. 
b. Grapefruit, grapefruit juice, grapefruit products, or herbal supplements with CYP 
altering abilities within 1 week prior to randomization (Day 1) or plans to 
consume during the study. 
c. CYP3A-sensitive substrates, including the opioids fentanyl and alfentanil, or 
moderate to strong CYP3A inhibitors or inducers within 28 days prior to 
randomization (Day 1) or plans to use during the study. 
d. Any drugs or substances known to be substrates or inhibitors of P-gp or BCRP 
within 28 days prior to randomization (Day 1) or plans to use during the study. 


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24. Receipt of erythropoietin, luspatercept (Reblozyl®), or other erythropoiesis-
stimulating or erythroid maturation agent within 6 months prior to signing the ICF or 
anticipated need for such agents during the study. 
25. Prior gene therapy. 
26. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from participating in the study, including the presence of 
laboratory abnormalities that may place the subject at unacceptable risk if he/she were 
to participate in the study. 
27. Other prior or ongoing medical condition, physical findings, or laboratory 
abnormality that, in the investigator’s opinion, could adversely affect the safety of the 
subject, make it unlikely that the course of treatment or follow-up would be 
completed, or impair the assessment of study results (e.g., a history of drug or alcohol 
abuse within the past 1 year, as judged by the investigator). 
8.3. 
Screen Failures 
Any subject who consents to participate in the study but is not randomized will be considered a 
screen failure. Demographic data, eligibility criteria, primary reason for screen failure, and any 
SAEs (if applicable) will be recorded and reported in the subject’s electronic case report form 
(eCRF) for subjects who are considered screen failures.  
If a subject is considered a screen failure, then he/she may be rescreened once with sponsor 
approval. 
8.4. 
Guidelines for Withdrawal of Subjects from Study Participation 
Subjects will be informed that they withdraw from participation in the study at any time and for 
any reason, without prejudice to further medical care. 
The investigator may also remove a subject from the study at their discretion if, in the 
investigator’s opinion, it is not in the best interest of the subject to continue in the study.  
If a subject must be withdrawn from study participation, the medical monitor should be informed 
and consulted regarding possible appropriate assessments to be completed in advance of study 
withdrawal. In case of withdrawal from the study, every effort will be made to complete both the 
early termination (ET) visit assessments and the EOS visit assessments, if possible. If a subject 
does not complete the ET assessments, every effort should be made to obtain the EOS 
assessments; in this case, the ET and EOS visits will coincide. If a final visit is not feasible, 
every effort to collect follow-up medical records will be attempted. 
In the case of subjects who are lost to follow-up, the study site must attempt to contact the 
subject by phone, making at least 3 documented attempts, each at least 1 week apart. 
Additionally, a registered letter must have been sent with a copy on file. The study site should 
only deem the subject as lost to follow-up no less than 30 days following the first documented 
phone call attempt, unless circumstances preclude this (e.g., phone service has been discontinued 
or there is other evidence that contact is not feasible). 


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If the subject withdraws from the study, the specific circumstances surrounding the withdrawal 
must be recorded in the subject’s eCRF. 
Refer to Section 8.6 for details on subject replacement. 
Justifiable reasons to discontinue a subject from treatment (Section 8.5) and/or from the study 
may include, but are not limited to the following: 
 The subject was erroneously included in the study (i.e., did not meet eligibility 
criteria) 
 The subject experiences an SAE assessed as possibly or probably related to study 
drug 
 The subject is unable to comply with the requirements of the protocol 
 The subject participates in another investigational study 
 The subject withdraws consent to participate in the study 
 A subject for whom the blind is intentionally or accidentally broken 
8.5. 
Guidelines for Study Drug Dose Withholding or Discontinuation 
In consultation with the medical monitor, the investigator may decide to withhold or discontinue 
study drug dosing in cases where tolerability or safety concerns emerge. Table 2 provides 
recommended guidelines for these decisions.  
If a study drug dosing is withheld due to an AE (Section 12), subjects who continue on the study 
will have all assessments (except study drug administration) performed as per protocol. 
If study drug dosing is discontinued for any reason, the specific circumstances surrounding the 
discontinuation must be recorded in the subject’s eCRF. Any subject who discontinues study 
drug dosing must also be withdrawn from the study; however, all appropriate safety assessments 
and follow-up should be completed prior to withdrawal (Section 8.4). 
Table 2: 
Safety Guidelines for Study Drug Dose Reduction, Withholding, or 
Discontinuation 
Dose Reduction 
Event 
Recommended Action 
A Grade 2 or higher TEAE that, in the opinion of 
the investigator, is both study drug related and 
that makes continued dosing at the current dose 
level inadvisable due to safety concern or lack of 
tolerability. 
Study drug may be reduced by 1 tablet for up to 
14 continuous days. 
If, in the opinion of the investigator, a longer dose 
reduction is clinically needed, the medical 
monitor should be contacted. 
If, in the opinion of the investigator, the severity 
of the Grade ≥2 TEAE has reduced to Grade ≤1, 
the subject may resume study drug at the original 
dose. If the TEAE recurs after re-introduction of 
the original dose, the subject should be withdrawn 
from the study. 


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Dose Interruption (Hold) 
 
Event 
Recommended Action 
A Grade 3 or higher TEAE that, in the opinion of 
the investigator, is both study drug related and 
that makes continued dosing at the current dose 
level inadvisable due to safety concern or lack of 
tolerability. 
Study drug should be held for up to 7 continuous 
days until reduction in severity of the TEAE to 
Grade ≤2, then resumed at the original dose. 
If, in the opinion of the investigator, dosing 
should be resumed at a lower dose, the medical 
monitor should be contacted. 
If, in the opinion of the investigator, a longer dose 
hold is clinically needed, the medical monitor 
should be contacted or the subject should be 
withdrawn from the study. 
Positive test results for COVID-19 and/or similar 
illness (asymptomatic and symptomatic). 
Study drug should be held until 7 days after 
subject tests negative. Please consult with the 
medical monitor if there are any questions 
regarding when to resume study drug. 
Abbreviations: COVID-19 = coronavirus disease 2019; TEAE = treatment-emergent adverse event. 
8.6. 
Replacement of Subjects 
If a subject withdraws or is withdrawn from the study at the discretion of the investigator or 
DMC up to and including the Week 12 visit, the subject may be replaced with another subject 
meeting the eligibility criteria. The replacement subject will receive the same treatment 
assignment as the replaced subject. Up to 10 subjects total may be replaced. Refer to Section 7 
and Section 10.1 for details about treatment assignments and randomization. Refer to Section 8.5 
for guidelines on study drug dose reduction, withholding, and discontinuation and to Section 8.4 
for guidelines on withdrawal of subjects from study participation. All data collected prior to 
withdrawal must be recorded in the replaced subject’s eCRF. 
8.7. 
Stopping Rules and Study Termination 
It is anticipated that AEs will occur frequently in this population based on the underlying disease, 
and that these can also be SAEs. There is no predefined type or frequency of AEs or SAEs for a 
stopping rule in this study. Review of SAEs and deaths on study will be performed routinely by 
the DMC, as defined in this protocol and in the DMC charter. 
If a safety concern arises that warrants review for possible study termination, the DMC (or party 
identifying such concern) will notify the sponsor immediately. Enrollment in the study may be 
temporarily halted for further review of safety data. This further assessment of safety data will 
include review by the DMC, which may include the recommendation to terminate the study 
early, as outlined in the DMC charter. 
Termination of the clinical study may also occur due to a regulatory authority decision or if the 
sponsor or regulatory authority decides that subject safety may be compromised by continuing 
the study. 


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If the study is halted temporarily or prematurely terminated, a written statement fully 
documenting the reasons for study halt or termination will be provided to the Institutional 
Review Board (IRB)/ Independent Ethics Committee (IEC) and appropriate regulatory 
authorities. 


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9. 
STUDY TREATMENTS 
9.1. 
Study Drug 
Study drug (IMR-687 or placebo) is to be taken as 2 tablets orally qd. 
IMR-687 will be supplied as 100, 150, or 200 mg white tablets. To optimize dosing, 60 kg will 
be used as the body weight gate for the administered tablet strength. Subjects in the lower dose 
group weighing <60 kg will be dispensed 100 mg tablets, and those weighing ≥60 kg will be 
dispensed 150 mg tablets. Subjects in the higher dose group weighing <60 kg will be dispensed 
150 mg tablets and those weighing ≥60 kg will be dispensed 200 mg tablets. The different doses 
of IMR-687 are visually identical in tablet form. 
Placebo will be supplied as white tablets containing matrix absent IMR-687. The placebo tablets 
are visually identical to the IMR-687 tablets. 
Subjects will be directed to take study drug (either IMR-687 or placebo) with food, but if a 
subject does not do so, it will not be considered a protocol deviation. 
9.2. 
Packaging and Labeling 
Finished tablets will be packaged in round, 60 cc high-density polyethylene bottles with a 
polypropylene cap. Each bottle contains 84 tablets. The bottles are induction sealed and capped. 
Each bottle will be labeled with a suitable Annex 13 country compliant product label.  
9.3. 
Storage Conditions 
Upon receipt of the study drug, an inventory must be performed, and a drug receipt log 
completed and signed by the person accepting the shipment. It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the shipment 
inventory. 
Only subjects enrolled in the study may receive study drug, and only authorized site staff may 
supply or administer study drug to subjects. All study drug must be stored in a secure, 
environmentally controlled, and monitored (manual or automatic) location in accordance with 
the labeled storage conditions and with access limited to the investigator and authorized site 
staff.  
The study site must maintain accurate records demonstrating dates and quantity of study drug 
received, to whom dispensed (subject-by-subject accounting), any amount returned, and accounts 
of any study drug that was accidentally destroyed. 
9.4. 
Administration 
Subjects will be advised to take 2 tablets (IMR-687 or matched placebo) orally qd during the 
treatment period. Subjects will be directed to take their study drug with food. On days when 
study drug is taken in the clinic, food details will also be recorded. 


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9.5. 
Treatment Compliance 
The investigator or designee must ensure that all subjects are adequately informed of study drug 
administration requirements for compliance/adherence with the study protocol. 
Treatment compliance/adherence with scheduled oral administration of study drug will be 
assessed at the study site starting at Week 4; all study drug administration will be documented on 
the appropriate pages of the eCRF. Subjects falling below an 80% treatment compliance rate 
between consecutive visits will be reported as a protocol deviation. 
9.6. 
Concomitant Medications 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject receives from the time of ICF signing through the 
end of the study must be recorded along with the following: 
 Reason for use 
 Dates and timing of administration, including start date/time and stop date/time 
 Dose and frequency of administration 
Subjects receiving HU must have received it continuously for at least 6 months prior to signing 
the ICF, and must have been on a stable dose for at least 3 months prior to signing the ICF, with 
no anticipated need for dose adjustments during the study including the screening period, in the 
opinion of the investigator. 
Over-the-counter medications such as analgesics and nonsteroidal anti-inflammatory drugs that 
are taken on an as-needed basis can be continued as long as they are not medications that 
interfere with metabolism, transport, or assessments (refer to Appendix 1 for additional 
information). All concomitant medications and/or therapies must be recorded on the appropriate 
pages of the eCRF. Use of any prohibited medication and/or therapy must also be recorded on 
the eCRF and must be documented as a protocol deviation. 
9.6.1. 
Non-investigational Medicinal Products 
Not applicable. 
9.6.2. 
Prohibited Concomitant Medications/Therapies 
The investigator, in consultation with the medical monitor, will determine if any of the following 
concomitant medications/therapies are necessary for the well-being of the subject. The subject 
will be withdrawn from the study if the following are determined to be necessary: 
 PDE5 inhibitors; any drugs or substances, including grapefruit juice or herbal 
supplements with CYP altering properties, that are known to strongly or moderately 
inhibit or induce CYP3A enzymes; and any drugs or substances that are substrates or 
inhibitors of P-gp or BCRP. Sensitive substrates of CYP3A4/5 are also prohibited. If 
there is any question as to whether a substance is permitted, please review the product 
labeling (if applicable) and consult the medical monitor and/or sponsor. 


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 Previous use (within 6 months prior to signing the ICF) or concomitant use of 
erythropoietin, luspatercept (Reblozyl®), or other erythropoiesis-stimulating or 
erythroid maturation agent. 
 Previous use (within 6 months prior to signing the ICF) or concomitant use of 
crizanlizumab (Adakveo®) or voxelotor (Oxbryta®). 
 Any other investigational drug or device. 
Because IMR-687 is a CYP3A4 substrate as well as a possible CYP3A4 inducer, caution should 
be employed in the co-administration of IMR-687 with other medications that are known 
CYP3A4 substrates. This potentially helps manage the competition for in vivo CYP3A4-
mediated clearance, which could result in a DDI. This approach includes applying caution with 
dosing other oral medications to minimize the chance of a drug interaction at the site of 
absorption (e.g., the GI tract). Additional information on potential drug interactions and how to 
proceed can be found in Section 5.2.3. 
Medications prohibited prior to study entry are described in the exclusion criteria in Section 8.2. 
9.6.3. 
Prohibited Concomitant Procedures 
Procedures prohibited prior to study entry are described in the exclusion criteria in Section 8.2. 
If a subject requires a blood transfusion at the Day 1 or Week 4 visit, the medical monitor should 
be notified, and the visit will be rescheduled while the subject proceeds with the transfusion. If a 
subject requires a blood transfusion during the study, the subject may continue to receive study 
drug and participate in the study. 
9.7. 
Handling and Disposal 
At the end of the study, a final reconciliation must be made between the quantity of study drug 
supplied, dispensed, and subsequently returned to the sponsor. A written explanation must be 
provided for any discrepancies. After accountability has been performed by the sponsor or 
sponsor’s designee, any unused study drug remaining at the end of the study will be returned to 
the sponsor for destruction. On-site destruction of unused study drug will be permitted with prior 
notice and approval from the sponsor. 


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10. 
RANDOMIZATION AND BLINDING 
10.1. 
Randomization 
All subjects who are screened (including screen failures) will be assigned a unique subject 
identification number. 
On Day 1, eligible subjects will be assigned another unique number (randomization number) in 
sequential order. The randomization number codes the subject’s initial treatment assignment 
according to the randomization schedule generated prior to the study. Randomization will be 
stratified by use of HU and by region (regions will be defined in the statistical analysis plan). 
Initially, subjects will be randomly assigned in a 2:1 ratio to receive either IMR-687 lower dose 
or placebo. If the DMC recommends inclusion of the higher dose, randomization will then 
proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose, or placebo).  
Randomization numbers will not be re-used once assigned. In the event that a subject is replaced 
(refer to Section 8.6), the replacement subject will receive the same treatment assignment as the 
replaced subject, and a different leading number will be used for the replacement randomization 
number. Additional details on randomization will be specified in the randomization plan 
provided by the interactive voice/web response system (IXRS) vendor. 
10.2. 
Blinding 
To ensure that the subject and site are blinded with respect to each subject’s treatment 
assignment, placebo tablets and tablets for each dose level of IMR-687 are identical in 
appearance and are supplied in identical packaging. Each bottle will contain a code that identifies 
the contents as either 100 mg IMR-687, 150 mg IMR-687, 200 mg IMR-687, or placebo. 
Every attempt should be made to preserve the integrity of study drug blinding. Except for cases 
of emergency unblinding, as described in Section 10.4, the randomization code will remain 
unbroken for subjects and study personnel at the site until the database has been locked. The 
blinded sponsor and contract research organization (CRO) study team members will be 
unblinded to the analysis results at the conclusion of the study (e.g., database lock). 
10.3. 
Unblinding for Interim Analyses 
To facilitate the IAs, certain sponsor representatives and designees will be unblinded to treatment 
assignments prior to and during the IAs (including the unblinded CRO biostatistician and 
external groups for bioanalytical, PK, and PK/PD analyses). Details will be provided in the study 
unblinding plan. 
10.4. 
Emergency Unblinding 
Unblinding is not always necessary to provide effective medical intervention and subject 
management in the event that a subject experiences a VOC, an SAE, or an event that results in 
cessation of treatment (see Section 8.7). However, in the exceptional circumstance in which the 
investigator believes that knowledge of the study drug assignment is essential to provide 
appropriate medical management, the treatment assignment for that subject will be provided to 
the investigator according to standard operating procedures at the CRO. The medical monitor 
and sponsor are available to the investigator as needed for any considerations of unblinding a 


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specific subject; however, the decision to unblind a specific subject relies solely on the clinical 
judgement of the investigator. That is, there is no requirement to discuss with the medical 
monitor and/or sponsor prior to unblinding a specific subject by the investigator; however, 
consultation is preferred. In the event that the investigator must unblind a subject and has not 
consulted with the medical monitor and/or sponsor, the investigator should notify the medical 
monitor and sponsor of the unblinding within 24 hours of breaking the blind. 
After breaking the blind, the site staff should record the reason(s) for breaking the blind and any 
AEs leading to the breaking of the blind in the source documents and the appropriate eCRF 
pages. After breaking the blind, the subject will be discontinued from the study and should 
proceed with the ET and EOS visits according to the schedule of assessments (Table 1). 


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11. 
ASSESSMENTS 
Refer to the schedule of assessments (Table 1) for the timing of the assessments described below. 
All data obtained from these assessments must be documented in the subject’s source 
documentation.  
Subjects should be seen for all visits on the designated day or within the defined allowable visit 
window (Table 1). The visits are as follows: 
 Screening (up to 28 days prior to Baseline) 
 Baseline (Day 1) 
 Treatment Period (Week 1 to Week 52) 
 Telephone visits will be performed at Week 2 and Week 6 
 EOT/ET (Week 52) 
 EOS (Week 56) 
Unless otherwise specified, all assessments should be completed prior to dosing at any given 
timepoint. 
11.1. 
Screening and Baseline Activities 
The descriptions below are for screening-specific activities. For descriptions of activities that 
occur during both the screening and treatment periods, refer to Section 11.2 for PD/efficacy 
assessments, Section 11.3 for safety assessments, and Section 11.4 for PK assessments. 
11.1.1. 
Informed Consent 
The subject must read, understand, and sign the IRB/IEC-approved ICF confirming his or her 
willingness to participate in this study before initiating any screening activity that is not standard 
of care. The investigator will ensure that the subject has received adequate language translation if 
needed and understands the ICF before signing as per the local IRB/IEC’s requirement. Subjects 
must also grant permission or be informed of national laws for the processing and dissemination 
of their personal data, including data concerning health (sensitive/protected health information) 
and the use and retention of their specimens for study-related purposes. 
11.1.2. 
Demographic Information and Medical/Disease History 
Subject demographics (age, sex, race, and ethnicity) and medical disease history (by thorough 
review of medical records and by interview) will be recorded at screening, in accordance with 
country requirements and institutional policies, and captured in the eCRF. Concurrent medical 
signs and symptoms must be documented to establish baseline severities.  
The diagnosis of SCD (HbSS, HbSβ0 thalassemia, or HbSβ+ thalassemia) should be confirmed in 
the medical record; if not available, the diagnosis must be confirmed at the site’s local laboratory 
instead. 


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11.1.3. 
Inclusion/Exclusion Criteria Evaluation 
Eligibility will be assessed based on the inclusion and exclusion criteria provided in Section 8. 
All inclusion and exclusion criteria will be assessed at the screening visit; continued eligibility 
based on these criteria will be confirmed on Day 1. 
11.1.4. 
Height 
Height in centimeters (cm) will be measured at the screening and EOT/ET visits (Table 1). 
11.1.5. 
Serum Virology 
Blood samples will be collected for serum virology (screening assessment) only if clinically 
indicated. Testing will be performed through a central laboratory and may include hepatitis B 
surface antigen (HBsAg), hepatitis A immunoglobulin M (IgM), and hepatitis C virus (HCV) 
antibody, as well as HIV testing. 
11.2. 
Efficacy and Pharmacodynamic Assessments 
11.2.1. 
Specialty Hematology 
Blood samples will be collected for HbF and % F-cells at selected study visits as shown in the 
schedule of assessments (Table 1). Refer to the specialty laboratory manual for details on the 
collection, handling, and processing of blood samples. 
11.2.2. 
Pharmacodynamic Assessments 
Blood samples will be collected for the following efficacy/PD laboratory assessments, many of 
which are routine clinical safety laboratory assessments, at selected study visits as shown in the 
schedule of assessments (Table 1). 
 Biomarkers of RBC hemolysis (% and absolute reticulocytes, unconjugated [indirect] 
bilirubin, and LDH) 
 Biomarkers of adhesion: soluble E-sel, P-sel, ICAM-1, and VCAM-1 
 Biomarkers of inflammation: hsCRP and MPO 
 Biomarker of cardiac stress: NT-proBNP 
 RBC indices (e.g., MCV) and total Hb 
Refer to Section 11.3.6 for additional details on clinical laboratory assessments. 
Refer to the central laboratory manual for details on the collection, handling, and processing of 
blood samples. 


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11.2.3. 
Clinical Assessment: VOCs 
VOC is defined as a documented episode of an acute painful crisis (for which there was not an 
explanation other than VOC) that involves moderate to severe pain lasting for at least 2 hours 
and at least one of the following: 
 Use of escalated analgesia (including healthcare professional-instructed use of an 
analgesic prescription) 
 A hospital, emergency department, or clinic visit and/or healthcare telephone 
consultation at the time of occurrence 
 Diagnosis of ACS (defined as an acute illness characterized by fever and/or 
respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray), 
hepatic sequestration, splenic sequestration, or priapism (in males) 
11.2.4. 
Quality of Life Assessments 
Data on QoL will be collected as per the schedule of assessments (Table 1). 
The Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me®) is a 
systematic, reliable, and valid method for documenting adult SCD patient-reported outcomes. 
The questions are grouped into 3 domains (physical, social, and emotional) encompassing 
7 subdomains, of which the following 5 will be measured: emotional impact, pain impact, sleep 
impact, social functioning impact, and stiffness impact. (Note: pain episodes and frequency, and 
SCD medical history checklist will not be evaluated). Each subdomain includes 5 to 9 items. 
Recall periods vary by subdomain and even question, with most of the periods being from 7 days 
to 30 days (Keller 2014). 
The Patient-Reported Outcomes Measurement Information System (PROMIS®), is a National 
Institutes of Health initiative to develop state-of-the-science self-report measures to assess 
functioning and well-being in physical, mental, and social domains of health. The PROMIS - 
Preference (PROMIS® 29 + 2 Profile v 2.1 [PROPr]) score can be estimated using the following 
7 PROMIS domains: cognitive function, emotional distress, fatigue, pain interference, physical 
function, ability to participate in social roles and activities, and sleep disturbance. Each domain 
is rated on a 5-point Likert scale. Recall periods vary by subdomain with most periods being in 
the past 7 days (Hanmer 2018). The translated QoL assessments from PROPr will be used when 
available. 
The Sickle Cell Self-Efficacy Scale (SCSES) is a 9-item QoL measure for adults with SCD. This 
measure is a self-appraisal of an SCD patient’s ability to engage in daily functional activities and 
to manage SCD symptomatology. Response choices range from “not at all sure” to “very sure” 
(Edwards 2000). 
11.3. 
Safety Assessments 
11.3.1. 
Telephone Visits 
Qualified site personnel will contact the subject by telephone at Week 2 and Week 6 to capture 
potential TEAEs and concomitant medications. Subjects will also be reminded of compliance 
with study drug and the next visit schedule. If any AEs of significant clinical concern are 


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identified during the telephonic visit, the subject will be requested to come into the site to be 
assessed. 
11.3.2. 
Vital Signs 
Vital signs include heart rate, respiratory rate, blood pressure, and body temperature and should 
be consistently measured in either the sitting or semi-supine position. Vital signs will be 
collected at every on-site visit (Table 1).At the Day 1 and Week 4 visits, vital signs will be taken 
pre-dose and 2 hours (±20 minutes) post-dose, during the PK assessments. At all other 
timepoints, vital signs can be taken irrespective of taking study drug. Vital signs that are 
clinically significant and not explained by the underlying disease or concomitant medications 
should be recorded as AEs in the eCRF. 
11.3.3. 
Weight 
Weight in kilograms (kg) will be measured at selected study visits as shown in the schedule of 
assessments. 
11.3.4. 
Physical Examination 
A complete PE will be conducted at selected study visits (including screening) as shown in the 
schedule of assessments (Table 1); at other visits, a symptom-driven PE may be conducted. The 
complete PE will include a general examination of the body, including the abdomen, heart, 
lungs, lymph nodes, back/neck, neurological system, skin, extremities, head, eyes, nose, and 
throat. 
During the course of the study, PEs will be symptom directed (except where indicated 
otherwise); symptom-directed PEs will be obtained after identification of AEs deemed by the 
investigator to be of significant clinical concern. 
Clinically significant findings that were present prior to the signing of informed consent must be 
included on the medical history eCRF. Clinically significant new findings that begin (or 
pretreatment findings that worsen) after signing the ICF and that meet the definition of AEs must 
be recorded on the AE eCRF. 
11.3.5. 
Electrocardiogram 
Triplicate 12-lead ECGs will be performed to evaluate the change from baseline in ECG 
parameters (heart rate, PR interval, RR interval, QRS duration, QT interval, and QTcF interval) 
at selected study visits as shown in the schedule of assessments. 
At the Baseline (Day 1), Week 1, and Week 4 visits, ECGs will be obtained pre-dose and 2 hours 
(±30 minutes) post-dose. At all other timepoints, ECG will be taken pre-dose. 
Interpretation of ECG tracings must be made by a qualified physician and documented on the 
ECG eCRF(s). The instrument used in the study to assess the ECG should be calibrated per the 
institution’s standard policy. 
Clinically significant abnormalities present prior to the subject’s signed informed consent should 
be reported on the Medical History eCRF. New or worsened clinically significant findings 
occurring after informed consent must be recorded on the AE eCRF as described in 
Section 12.1.1. 


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11.3.6. 
Laboratory Assessments 
Blood and urine samples will be collected for routine clinical safety laboratory assessments 
according to the schedule of assessments. Clinical safety tests will be assessed to evaluate 
IMR-687 safety and tolerability. Some of these tests are also considered efficacy assessments.  
For both safety and efficacy evaluations, laboratory tests specified in the protocol will be 
performed by a central laboratory. Because knowledge of certain laboratory assessments (HbF, 
% F-cells, MCV, total and unconjugated [indirect] bilirubin, and absolute and % reticulocyte 
count) may unblind the treatment assignment, these measurements will be blinded at the central 
laboratory. Based on predefined safety laboratory alerts, these blinded laboratory assessments 
may be communicated to the investigator. 
All abnormal clinical laboratory pages should be initialed and dated by an investigator, along 
with a comment regarding clinical significance. Each clinically significant laboratory result is to 
be recorded as medical history at screening and as an AE subsequently. If known, the diagnosis 
associated with an abnormality in clinical laboratory results considered clinically significant by 
the investigator should be recorded on the AE eCRF. 
11.3.6.1. Hematology 
Hematology assessments will be performed through a central laboratory and will include the 
following: RBC count (MCV, mean corpuscular Hb, and mean corpuscular Hb concentration), 
hematocrit (Hct), Hb, HbF, platelets, absolute WBC count (with differential: basophils, 
eosinophils, neutrophils, monocytes, and lymphocytes), erythrocyte count, reticulocyte count, 
and reticulocyte percentage. Some of these assessments are also considered efficacy/PD 
endpoints (refer to Section 11.2). 
11.3.6.2. Coagulation 
Coagulation assessments will include prothrombin time (PT), activated partial thromboplastin 
time (aPTT), and international normalized ratio (INR).  
11.3.6.3. Serum Chemistry 
Serum chemistries will be performed through a central laboratory and will include but not be 
limited to the following: ALT, albumin, alkaline phosphatase (ALP), AST, bicarbonate, blood 
urea nitrogen (BUN), chloride, calcium, creatinine, glucose, LDH, sodium, potassium, 
magnesium, phosphate, bilirubin (total, direct, and indirect), creatine kinase, total protein, eGFR, 
and gamma-glutamyl transferase (GGT). FSH is added for post-menopausal women at screening. 
Some of these assessments are also considered efficacy/PD endpoints (refer to Section 11.2). 
11.3.6.4. Urinalysis 
Urine will be assessed for appearance, color, pH, specific gravity, ketone, protein, glucose, 
bilirubin, and urobilinogen, including occult blood and microscopic examination of sediment 
(only if occult blood is detected). Urine creatinine, Pr:Cr ratio, and microalbumin will be 
completed with each analysis. 


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11.3.6.5. Pregnancy Test 
Serum pregnancy tests will be performed during screening via a central laboratory for all female 
subjects of childbearing potential who are not post-menopausal or surgically sterile. All 
subsequent pregnancy tests will be urine pregnancy tests performed locally (with test kits 
provided by the central laboratory). If a urine pregnancy test is positive, the result must be 
confirmed with a serum pregnancy test. 
11.3.7. 
Adverse Event Collection 
Details of AE data collection are described in Section 12. AEs will be collected at every visit. 
11.3.8. 
Concomitant Medications 
Concomitant medications will be recorded at every visit in the medical record and on the 
appropriate eCRF. Any additions, discontinuations, or changes of these medications will be 
documented. 
11.4. 
Pharmacokinetics Assessments 
Serial blood samples will be collected at the timepoints indicated in the schedule of assessments 
for the determination of IMR-687 plasma concentrations (including metabolites and HU, if 
applicable). Trough blood samples (pre-dose) will be drawn at the specified timepoints (Table 1). 
The date/time of the last administered dose will be recorded. 
Refer to the laboratory manual for details on the collection, handling, and processing of blood 
samples. 


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12. 
SAFETY MONITORING AND REPORTING 
12.1.1. 
Adverse Event and Serious Adverse Event Collection 
12.1.1.1. Time Period Adverse Event Collection 
All AEs and SAEs, related and unrelated, will be recorded from the signing of informed consent 
through the EOS safety follow-up visit. Events that occur following administration of study drug 
will be considered TEAEs.  
All SAEs will be recorded and reported to the sponsor or sponsor’s designee within 24 hours, as 
indicated in Section 12.1.2.3. The investigator will also submit any updated SAE data to the 
sponsor within 24 hours of the data being available. 
12.1.1.2. Follow-up 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits and phone contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the subject is lost to follow-up. 
12.1.2. 
Adverse Event Recording and Reporting 
12.1.2.1. Definitions 
12.1.2.1.1. Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a clinical study subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable or unintended sign (for example, an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
Examples of AEs include, but are not limited to, the following: 
 Abnormal test findings 
 Clinically significant symptoms and signs 
 Changes in PE findings 
 Hypersensitivity 
 Drug abuse 
 Drug dependency 
Additionally, AEs may include the signs or symptoms resulting from: 
 Drug overdose 
 Drug withdrawal 
 Drug misuse 


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 Drug interactions 
 Extravasation 
 Exposure during pregnancy 
 Exposure via breastfeeding 
 Medication error 
12.1.2.1.2. Definition of a Serious Adverse Event 
An SAE is any AE that results in one or more of the following outcomes: 
 Death 
 Requires or prolongs hospitalization (In general, hospitalization signifies that the 
subject has been detained, usually involving at least an overnight stay, at the hospital 
or emergency ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfils 
any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious.) 
 Is life-threatening (In general, an AE is considered to be life-threatening if the 
subject is at immediate risk of death. It does not include an AE that, had it occurred in 
a more severe form, might have caused death.) 
 Persistent or significant disability/incapacity (In general, this means a substantial 
disruption of a person’s ability to conduct normal life functions. This definition is not 
intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, or accidental trauma 
[e.g., sprained ankle] that may interfere with or prevent everyday life functions, but 
do not constitute a substantial disruption.) 
 Congenital anomaly or birth defect (that occurs in the offspring of a subject 
exposed to the investigational product) 
 Other medically important event (In general, this means an AE that, based upon 
appropriate medical judgment, is considered to jeopardize the subject’s safety and may 
require medical or surgical intervention to prevent one of the outcomes listed above.) 
Reporting requirements for SAEs are described in Section 12.1.2.3. 
12.1.2.1.3. Definition of a Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is an SAE that, in the opinion of the 
investigator, is believed with reasonable probability (i.e., is suspected) to be due to the 
investigational product, but the nature or severity of which is not consistent with the reference 
safety information (i.e., is unexpected). 
Reporting requirements for SUSARs are described in Section 12.1.2.4. 


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12.1.2.2. Evaluation of Adverse Events/Serious Adverse Events 
12.1.2.2.1. Assessment of Severity 
AE severity (intensity) will be graded using National Cancer Institute Common Terminology for 
Adverse Events (NCI CTCAE), version 5.0 (Appendix 2). The CTCAE is a descriptive 
terminology utilized for AE reporting. A grading scale is provided for each AE term.  
Grade refers to the severity (intensity) of the AE. The CTCAE provides unique clinical 
descriptions of severity for each AE based on the following general guideline: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL* 
Grade 3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL** 
Grade 4 
Life-threatening consequences: urgent intervention indicated 
Grade 5 
Death related to AE 
ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
Note: The CTCAE terminology provides grading for specific laboratory test abnormalities (Appendix 2). Grade 4 laboratory 
abnormalities do not automatically signify life-threatening AEs. Abnormal laboratory test results will be considered AEs only if 
the investigator, based on his or her medical judgement, deems the abnormality to be clinically significant. 
Change in severity of an AE should be documented based on specific guidelines in the eCRF 
Completion Guidelines. 
Severity and seriousness must be differentiated: Severity describes the intensity of an AE, while 
the term seriousness refers to an AE that has met the criteria for an SAE (defined in 
Section 12.1.2.1.2). 
12.1.2.2.2. Assessment of Causality 
The investigator will assess the potential relatedness of each AE to the investigational product. 
An investigator causality assessment (unlikely/not related, possible, probable/likely, or 
certain/related) must be provided for all AEs (both serious and non-serious). This assessment 
must be recorded on the eCRF and any additional forms as appropriate. 
Unlikely/Not Related: 
 
Event or laboratory test abnormality, with a time to drug intake 
that makes a relationship improbable (but not impossible) 
 
Disease or other drugs provide plausible explanations 
Possible: 
 
Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
 
Could also be explained by disease or other drugs 
 
Information on drug withdrawal may be lacking or unclear 


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Probable/Likely: 
 
Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
 
Unlikely to be attributed to disease or other drugs 
 
Response to withdrawal clinically reasonable 
 
Rechallenge not required 
Certain/Related: 
 
Event or laboratory test abnormality, with plausible time 
relationship to drug intake 
 
Cannot be explained by disease or other drugs 
 
Response to withdrawal plausible (pharmacologically, 
pathologically) 
 
Event definitive pharmacologically or phenomenologically 
(i.e., an objective and specific medical disorder or a recognized 
pharmacological phenomenon) 
 
Rechallenge satisfactory, if necessary 
12.1.2.2.3. Outcome of Adverse Events 
Outcome describes the status of the AE. Once the outcome is clear or at the end of the study, the 
investigator assigns one of the following outcomes for each AE: fatal, not recovered/not resolved, 
recovering/resolving, recovered/resolved, recovered/resolved with sequelae, or unknown. 
12.1.2.3. Recording and Reporting Adverse Events and Serious Adverse Events 
All AEs, both serious and non-serious, must be recorded in the eCRF.  
Study site personnel must notify the sponsor or its designee of any SAE within 24 hours of 
becoming aware of the event. The notification must occur via a sponsor-approved (official) 
method. If the sponsor or its designee is initially notified by telephone, the phone call is to be 
immediately followed by notification via sponsor-approved method. The investigator must 
complete, sign, and date the SAE pages; verify the accuracy of the information recorded on the 
SAE pages with the corresponding source documents; and send a copy via email. Facsimile 
transmission may be used in the event of electronic submission or email failure. 
Safety Reporting: North America  
Telephone: +1 800 772 2215 or +1 434 951 3489 
Fax: +1 888 772 6919 or +1 434 951 3482 
Safety Reporting: Europe, Middle East, Africa, and Asia-Pacific 
Telephone: +49 621 878 2154 
Fax: +44 1792 525 720 
Initial SAE reports must be followed by detailed descriptions. These should include copies of 
de-identified hospital case records and other documents when requested. If further information 
becomes available, the SAE Form should be updated with the new information and reported. The 
24-hour notification requirement refers to reporting both initial SAE information and all 
follow-up SAE information once the site is made aware. 


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SAEs occurring up to and including the subject’s last study visit will be collected, regardless of 
the investigator’s opinion of causation. A death occurring during the study and within 30 days 
after the last study visit must be reported to the sponsor or its designee with 24 hours of 
knowledge of the death, regardless of causality. In addition, if the investigator learns of any 
SAE, including a death, at any time after a subject has been discharged from the study, and 
he/she considers the event to be reasonably related to the study drug or study participation, the 
investigator must promptly notify the sponsor. 
For all SAEs, the investigator must provide the following: 
 Appropriate and requested follow-up information in the timeframe detailed above 
 Causality of the SAE(s) 
 Outcome of the SAE(s) 
 Medical records and laboratory/diagnostic information 
12.1.2.4. Regulatory Reporting Requirements 
Sponsor’s Reporting Requirements 
The sponsor or its legal representative is responsible for notifying the relevant regulatory 
authorities of SAEs and SUSARs meeting the reporting criteria. This protocol will use the 
current IB as the Reference Safety Document. The expectedness and reporting criteria of an SAE 
will be determined by the sponsor from the Reference Safety Document. 
Investigator’s Reporting Requirements 
The investigator must fulfill all local regulatory obligations required of investigators for the 
study. It is the investigator’s responsibility to notify the IRB/IEC of all SAEs that occur at his or 
her site. Investigators will also be notified of all SUSARs that occur during the clinical study. 
Investigators will receive blinded information unless unblinded information is judged necessary 
for safety reasons. 
12.1.2.5. Exposure During Pregnancy 
Pregnancy data will be collected for all subjects. Exposure during pregnancy (also referred to as 
exposure in utero) can be the result of either maternal exposure or transmission of the 
investigational product via semen following paternal exposure. 
Exposure during pregnancy must be recorded, and the subject must be followed until the 
outcome of the pregnancy is known (spontaneous miscarriage, elective termination, normal birth, 
or congenital abnormality) even though the subject will be withdrawn from the study per 
Section 8.4. 
If a subject or a subject’s partner becomes pregnant while treated or exposed to investigational 
product, the investigator must submit a pregnancy form to the sponsor via the same method as 
SAE reporting. When the outcome of the pregnancy becomes known, the form should be 
completed and returned to the sponsor or the sponsor’s designee. If additional follow-up is 
required, the investigator will be requested to provide the information. 


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12.1.3. 
Medication Error and Reporting 
In the event of a medication error, including overdose (accidental or intentional), it will be 
captured as an AE. A medication error associated with an SAE (including overdose, inadvertent 
exposure, and/or accidental exposure) will also be reported (see Section 12.1.2.3). 
Medication errors that result, for example, from the administration or consumption of the wrong 
drug, by the wrong subject, at the wrong time, or at the wrong dosage strength will also be 
captured as a protocol deviation. In the event of medication dosing error or an overdose, the 
medical monitor and sponsor should be notified immediately.  
Medication errors are reportable irrespective of the presence of an associated AE/SAE, including 
the following: 
 Medication errors involving subject exposure to the product.  
 Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject. 
The sponsor does not recommend specific treatment for an overdose with IMR-687. Decisions 
regarding dose withholding will be made by the investigator in consultation with the medical 
monitor based on the clinical evaluation of the subject. 
Whether or not the medication error is accompanied by an AE, the medication error and, if 
applicable, any associated AE(s), is captured as an AE.  


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13. 
STATISTICS 
13.1. 
General Considerations 
Descriptive summary statistics will be provided for demographics, disposition, and treatment 
exposure. The number and percentage of subjects who discontinue from the study, along with 
reasons for discontinuations will be tabulated. 
Continuous variables will be summarized using descriptive statistics (number of subjects, mean, 
standard deviation [SD], median, first quartile [Q1], third quartile [Q3], minimum, and 
maximum) and, where appropriate, coefficient of variation (%CV) and graphic representation. 
Categorical data will be summarized by sample size and proportions. 
An IA will be performed after all randomized subjects have reached Week 24 or terminated 
early. Alpha spending will be needed based on the results of these analyses. A final analysis (FA) 
will be conducted at study completion (i.e., when all subjects have reached Week 56 or 
terminated early). 
13.2. 
Analysis Datasets 
The safety analysis set will include all subjects who have received any amount of study drug and 
from whom informed consent has been obtained. The safety analysis set will be used to 
summarize all safety and tolerability data. In safety data summaries, subjects will be analyzed 
according to the actual treatment they received. 
The PK analysis set will be defined as a subset of the safety analysis set that includes all subjects 
who are enrolled in the study, have received at least 1 dose of IMR-687, and have any 
measurable IMR-687 concentration-time data; this set will be used to generate the corresponding 
PK concentration summaries and plots.  
The PK evaluable set will be defined as a subset of the safety analysis set that received at least 
1 dose of IMR-687 and has at least 4 consecutive non-zero post-dose IMR-687 concentration-
time data points. The PK Evaluable Set will be used to generate the corresponding PK exposure 
(parameter) assessments.  
The intent-to-treat (ITT) set will include all randomized subjects. The ITT set will be used as the 
primary analysis set to summarize efficacy, PD, and clinical outcome parameters. Subjects will 
be analyzed according to their randomized treatment assignment.  
The modified intent-to-treat (mITT) set will include all randomized subjects who had at least 
1 VOC in the 12 months prior to randomization and have received at least 1 dose of study drug. 
The mITT set will be used for sensitivity analyses of efficacy, PD, and clinical outcome 
parameters. Subjects will be analyzed according to their randomized treatment assignment. 
The per protocol (PP) set will include all subjects of the safety analysis set who had at least 
1 VOC in the 12 months prior to randomization, completed at least 1 valid clinical outcomes 
assessment without major protocol deviations or events that would be expected to affect the 
analysis and did not discontinue prior to Week 24 for reasons other than AEs. The PP set will be 
identified based on blinded data prior to unblinding the mITT dataset. The PP set will be used for 
sensitivity analyses of efficacy, PD, and clinical outcome parameters. 


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13.3. 
Safety Analyses 
Descriptive statistics will be used to summarize all safety endpoints, by treatment group as 
appropriate. Data summaries will be displayed for incidence of AEs, clinical laboratory 
variables, vital signs, and ECG parameters. 
Safety data summaries will use the safety analysis set. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Data 
will be summarized using preferred term and primary system organ class. AE summaries will 
include AEs leading to study discontinuation and severity and frequency of AEs and SAEs. 
All safety data will be summarized in by-subject listings. 
13.4. 
Efficacy Analyses 
Primary Efficacy Analysis 
The primary efficacy endpoint, annualized rate of VOCs, will be analyzed using a stratified 
Wilcoxon rank-sum test based on stratification factors of region (North America/Europe versus 
Africa/Middle East) and HU use (Yes versus No) to compare the treatment effect of the highest 
tolerated dose of IMR-687 to placebo. VOCs are defined for this study in Inclusion Criterion 3 
(Section 8.1).An IA will be performed after all randomized subjects have reached Week 24 or 
terminated early. A Lan-DeMets alpha spending function will be used to determine the 
significance levels for the IA  to maintain an overall type I error rate of 5% for 2-sided tests. 
Secondary Efficacy Analyses 
The first key secondary efficacy endpoint, time to first VOC, will be analyzed using a stratified 
log rank test (stratification factors of HU use and region) and stratified Cox regression model to 
compare the treatment effect of the highest tolerated dose of IMR-687 to placebo.  
The second key secondary efficacy endpoint, proportion of HbF responders (defined as the 
proportion of subjects with an absolute increase of ≥3% in HbF from baseline) at Week 24, will 
be analyzed using a stratified Cochran-Mantel-Haenszel (CMH) test based on stratification 
factors of HU use and region to compare the highest tolerated dose of IMR-687 to placebo. 
Other secondary endpoints that will be tested at the highest tolerated dose include the following: 
 Proportion of VOC-free subjects 
 Annualized rate of hospitalizations for VOCs 
 Time to second VOC 
 Proportion of HbF responders (defined as the proportion of subjects with an absolute 
increase of ≥3% in HbF from baseline) at Week 52 
 Change from baseline in HbF (%) and F-cells (%) at Week 24 and Week 52 
 Proportion of Hb responders (defined as the proportion of subjects with an increase of 
≥1.0 g/dL in total Hb from baseline) at Week 24 and Week 52 
 Change from baseline in total Hb (g/dL) at Week 24 and Week 52 


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 Change from baseline in biomarkers of RBC hemolysis (% and absolute reticulocytes, 
unconjugated [indirect] bilirubin, and LDH) at Week 24 and Week 52 
 Change from baseline in each measured subdomain of the ASCQ-Me® questionnaire 
at Week 24 and Week 52 
 Change from baseline in total preference score and individual domain scores of the 
PROPr questionnaire at Week 24 and Week 52 
 Change from baseline in overall score of the SCSES at Week 24 and Week 52 
 Change from baseline in biomarkers of adhesion such as soluble E-sel, P-sel, 
ICAM-1, and VCAM-1 at Week 24 and Week 52 
 Change from baseline in biomarkers of inflammation such as hsCRP and MPO at 
Week 24 and Week 52 
 Change from baseline in biomarkers of cardiac stress such as NT-proBNP at Week 24 
and Week 52 
 Change from baseline in RBC indices, such as MCV, at Week 24 and Week 52 
The secondary endpoints of proportion of HbF responders at Week 52 and proportion of Hb 
responders at Week 24 and Week 52 will each be analyzed in a similar manner as the second key 
secondary efficacy endpoint using a stratified CMH test based on stratification factors of HU use 
and region. 
The annualized rate of hospitalizations for VOCs will be analyzed using a stratified Wilcoxon 
rank-sum tests based on stratification factors of HU use and region. 
Change from baseline endpoints for continuous variables will be analyzed using mixed models 
for repeated measures (MMRM) with treatment, visit, and treatment-by-visit interaction as fixed 
effects, and baseline value, HU use, and region as covariates. Unstructured covariance matrices 
will be used. If there are convergence problems, then the use of other covariance matrices will be 
considered as appropriate. 
Time-to-event endpoints will be analyzed using log-rank tests, and Kaplan-Meier plots will be 
provided. 
An FA will be conducted at study completion (i.e., when all subjects have reached Week 56 or 
terminated early). A Lan-DeMets alpha spending function will be used to determine the 
significance levels for the IA and FA to maintain an overall type I error rate of 5% for 2-sided 
tests. At the FA endpoints will be tested in a sequential hierarchical order at the highest tolerated 
dose. 
13.5. 
Pharmacokinetic Analyses 
Summary statistics for trough (Ctrough) and other plasma concentration data will be provided. 
Accumulation may be assessed. PK data from this study will also be used to explore any 
relationship between IMR-687 exposure and clinical response, PD endpoints, or AEs, as data 
permit. These data will be analyzed together with the PK data from other clinical studies for a 
population PK analysis, as appropriate. 


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13.6. 
Analyses of Exploratory Endpoint 
Change from baseline in renal function as measured by the urine Pr:Cr ratio and microalbumin at 
Week 24 and Week 52 will be summarized with descriptive statistics by treatment group. 
The statistical analysis plan will provide further details regarding the definition of analysis 
variables and analysis methodology to address all study objectives.  
13.7. 
Sample Size Calculation 
The sample size of this study was previously determined based on HbF responder rate, 
comparing the highest tolerated dose of IMR-687 to placebo, as the primary endpoint:  
The sample size was determined assuming that the percentage of subjects who are HbF 
responders (i.e., have an HbF increase of ≥3% from baseline) at Week 24 is 5% in the placebo 
arm and 35% in either of the IMR-687 arms, with a 20% dropout rate prior to Week 24. Based 
on these assumptions, 26 subjects/arm at Week 24 is sufficient to achieve 80% power to detect a 
difference between the highest tolerated IMR-687 dose and placebo in the HbF responders at 
Week 24 at a 2-sided significance level of 0.05. 
Based on regulatory feedback, annualized rate of VOCs was elevated from a key secondary 
endpoint to the primary endpoint, with a corresponding change in statistical methodology:  
Assuming that the actual data distribution is normal when the significance level (alpha) of the 
test is 0.05, the standard deviation is 2.7 in both groups, and there are no dropouts, there will be 
88% power to detect a difference between the medians of 5.0 and 3.0 for the placebo and the 
IMR-687 highest tolerated dose groups, respectively (i.e., a 40% difference), using a 2-sided 
Wilcoxon rank-sum test.  
 


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14. 
DATA COLLECTION AND QUALITY CONTROL  
Data collection is the responsibility of the staff at the study site under the supervision of the 
investigator. The designated study site staff will enter the data required by the protocol into the 
eCRFs. The eCRF is the primary data collection instrument for the study. The eCRFs have been 
built using fully validated secure web-enabled software that conforms to US Code of Federal 
Regulations (CFR) Title 21 Part 11 requirements. The investigator should ensure the accuracy, 
completeness, legibility, and timeliness of the data reported in the eCRFs and all other required 
reports. Data reported on the eCRF that are derived from source documents should be consistent 
with the source documents, or the discrepancies should be explained. All data requested on the 
eCRF must be recorded. Any missing data must be explained. For eCRFs, an audit trail will be 
maintained by the system to capture data changes. Study site staff will not be given access to the 
electronic data capture system until they have been trained. Automatic validation programs will 
check for data discrepancies in the eCRFs and allow modification or verification of the entered 
data by the study site staff. 
The investigator is responsible for assuring that the data recorded on eCRFs are complete and 
accurate, and that entry and updates are performed in a timely manner. 
14.1. 
Database Management and Data Quality Control 
The sponsor or designee will review the data entered by investigational staff for completeness 
and accuracy. Electronic data queries stating the nature of the problem and requesting 
clarification will be created for discrepancies and missing values by generating appropriate error 
messages. In addition, the outsourced vendor Data Management staff will review the data using 
validation programs and database listings and enter electronic queries for discrepancies allowing 
modification or verification of the entered data by the designated study staff. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Medical history and AEs will be coded using the MedDRA 
terminology. 
14.2. 
Study Site Monitoring 
Before study initiation at a study site, sponsor personnel or designee will review the protocol and 
eCRFs with the investigators and their study staff during an initiation visit or at an investigator’s 
meeting. During the study, the blinded clinical monitors will visit the study site regularly to 
check the completeness of subject records, the accuracy of entries on the eCRFs, the adherence 
to the protocol and Good Clinical Practice (GCP), and the progress of enrollment. The monitors 
will also ensure that study drug is being stored, dispensed, and accounted for according to 
sponsor specifications. Key study personnel must be available to assist the clinical monitors 
during these visits. 
The investigator must maintain source documents for each subject in the study, consisting of 
hospital or clinic medical records including, but not limited to, demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information recorded on eCRFs must be traceable to source documents in the subject’s file. The 


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investigator must also keep the original signed ICF (a signed and dated copy is given to the 
subject/legally authorized representative). 
The investigator must give the clinical monitors access to all relevant source documents to 
confirm their consistency with the eCRF entries. Monitoring standards require verification for 
the presence of signed/dated informed consent, adherence to the inclusion/exclusion criteria, and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. 
14.3. 
Subject Data Protection and Confidentiality  
Information about study subjects will be obtained, processed, kept confidential, and protected 
according to the applicable laws and regulations, such as the US Health Insurance Portability and 
Accountability Act of 1996 (HIPAA) or General Data Protection Regulation (GDPR) on the 
protection of natural persons with regard to the processing of personal data and on the free 
movement of such data. 
Those regulations require a signed and dated subject consent or a notice informing the subject of 
the following: 
 The sponsor’s (i.e., Data Controller’s) identity. 
 The European Union Data Protection Representative’s identity. 
 Contact information for the Data Protection Officer of the site and the Data 
Controller. 
 The right to complain with a Data Protection Authority and the address of it. 
 What personal data, including sensitive/personal health information, will be collected 
from subjects in the study and for what purpose. 
 Who will have access to that information and why. 
 Who will process or disseminate that information. 
 The right of a research subject to discontinue study participation and revoke consent 
at any time for any reason. 
Note: In the event that a subject revokes consent, the investigator retains the ability to 
use all information collected prior to the revocation. For subjects who have revoked 
consent, attempts should be made to obtain permission to collect follow-up safety 
information (e.g., has the subject experienced any new or worsened AEs) at the end 
of their scheduled study period. 
 Possible risks to the subject associated with the transfer of his/her data to third 
countries or international organizations. 
 The suitable safeguards implemented to protect subject confidentiality and ensure 
subject data protection. 
 An explanation that study subjects who do not consent to the forwarding of such data 
will not be included in the clinical study. 


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The data collection system for this study uses built-in security features to encrypt all transmitted 
data, preventing unauthorized access to confidential subject information. Access to the system 
will be controlled by a sequence of individually assigned user identification codes and 
passwords, made available only to authorized personnel. 
In order to maintain subject confidentiality and to ensure subject data protection, the system will 
not solicit subject’s initials or exact date of birth. Instead, each subject will be identified by a 
subject identification number, and age will be solicited to establish that the subject satisfies 
protocol age requirements. 
Any subject-related study documents sent to the sponsor (or designee) must be pseudonymized, 
i.e., must not contain direct identifiers such as subject’s name, initials, date of birth, etc. 


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15. 
ADMINISTRATIVE, ETHICAL, AND REGULATORY 
CONSIDERATIONS 
15.1. 
Protocol 
15.1.1. 
Protocol Amendments 
Any change to the protocol will be in the form of a written protocol amendment or administrative 
change document that will be issued by the sponsor or designee. 
Amendments specifically affecting the safety of subjects, the scope of the investigation, or the 
scientific quality of the study require additional approval by the applicable IRB(s)/IEC(s) of all 
study sites. Sites will not implement the protocol changes as described in an amendment until 
both regulatory authority and IRB/IEC approvals have been received. 
The protocol requirements should in no way prevent any immediate action from being taken by 
the investigator/medically qualified designee (must be MD), or by the sponsor (or designee), in 
the interest of preserving the safety of subjects included in the study. Changes affecting only 
administrative aspects of the study do not require formal protocol amendments or IRB/IEC 
approval, but the IRB/IEC must be kept informed of such changes. Therefore, the study site will 
send the administrative change document to the IRB/IEC according to the IRB’s/IEC’s 
documented process. 
15.1.2. 
Protocol Adherence 
It is the responsibility of the investigators to apply due diligence to avoid protocol deviations. If 
protocol deviations are identified, the sponsor or designee may be consulted to determine the 
best course of action to protect subject safety and maintain the integrity of the study data. The 
sponsor does not anticipate approving protocol deviations (i.e., waiving of inclusion/exclusion 
criteria or planned protocol deviations). If the investigator feels a protocol deviation would 
improve the conduct of the study, this must be considered a protocol amendment, and unless 
such an amendment is agreed upon by the sponsor and approved by the regulatory authority and 
IRB/IEC, it cannot be implemented. All significant protocol deviations will be recorded and 
reported in the clinical study report. 
15.1.3. 
Discontinuation of Site Participation 
If, in the opinion of the investigator or sponsor, the clinical observations in the study suggest that 
it may be unwise to continue, the investigator may discontinue their participation in the study. A 
written statement fully documenting the reasons for discontinuation will be provided to the 
sponsor (or designee) and IRB/IEC. 
15.1.4. 
Protocol Disclosure and Confidentiality 
This protocol will be registered and maintained on ClinicalTrials.gov and other regulatory 
registries in accordance with applicable regulations. 
The contents of this protocol and any amendments and results obtained during the course of this 
study will be kept confidential by the investigator, the study site staff, and IRB/IEC and will not 
be disclosed in whole or in part to others or used for any purpose other than reviewing or 


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performing the study without the written consent of the sponsor. Accordingly, the investigator is 
prohibited from publishing any data collected or results obtained during the course of this study 
without the prior written approval of the sponsor. These obligations of confidentiality and 
non-use shall in no way diminish such obligations as set forth in the confidentiality agreement 
between the sponsor and the investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in the confidentiality agreement between the investigator 
and sponsor or designee. 
15.2. 
Institutional Review Board or Independent Ethics Committee 
The protocol, any protocol amendments, and the ICF will be reviewed and approved by each 
site’s IRB/IEC before subjects are screened for entry into the study. Verification of the 
IRB’s/IEC’s unconditional approval of the protocol will be transmitted to the sponsor (or 
designee) prior to the study site(s) being initiated. The investigator(s) will submit, depending on 
local regulations, periodic reports and inform the IRB/IEC of any reportable AEs per 
International Council for Harmonisation (ICH) guidelines and local IRB/IEC standards of 
practice. 
A list of IRBs/IECs that approved this study will be included in the clinical study report. 
15.3. 
Ethical Conduct of the Study 
The study will be conducted in accordance with this protocol and applicable country-specific 
laws and regulations, including, but not limited to, the following: 
 US CFR 
 ICH E6(R2) Good Clinical Practice: Consolidated Guidance (GCP) 
 Declaration of Helsinki (“Recommendations Guiding Physicians in Biomedical 
Research Involving Human Patients”) and all its accepted amendments to date 
concerning medical research in humans 
15.4. 
Subject Informed Consent 
In accordance with ICH E6 (Section 4.8) and US CFR Title 21 Part 50, informed consent will be 
documented by the use of a written ICF approved by the IRB/IEC prior to protocol-specific 
procedures being performed. 
The investigator (or designee) will explain the nature of the study and the action(s) of IMR-687. 
The subjects will be informed that participation is voluntary and that they can withdraw from the 
study at any time. They will be provided ample time and opportunity to inquire about details of 
the study and to decide whether or not to participate in the study. 
The subjects must read, understand, sign, and date the IRB/IEC-approved ICF confirming their 
willingness to participate in this study before any screening activity that is not standard of care is 
initiated. Subjects must also agree and grant permission for the collection, use, and retention of 
their biological samples, as applicable, until the end of the study when select samples will be 
analyzed, and to the processing and dissemination of their personal data, including data 


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concerning health (sensitive/protected health information). Specifically, in relation to biological 
samples, once study-related testing has been completed, any remaining samples will be destroyed 
in compliance with the subject informed consent and applicable law. Samples will not be 
processed for future use. The subjects or their guardians/legally authorized representatives will 
be given a signed and dated copy of the ICF and any other written subject information, and the 
original ICF will be maintained at the study site with the subjects’ records. 
The investigator must ensure that the subject has received adequate language translation, if 
needed, and understands the ICF before signing as per the local IRB’s/IEC’s requirement. 
Subjects who refuse to have their biological specimens collected and retained until the end of the 
study when select samples will be analyzed, and/or who do not agree and grant permission for 
the processing and dissemination of their personal data, including data concerning health 
(sensitive/protected health information), may not participate in the study. 
15.5. 
Publication of Study Protocol and Results 
The sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as ClinicalTrials.gov. The clinical study report will be submitted to the 
IRBs/IECs and regulatory authorities within 1 year of the end of the study (worldwide). 
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor. 
15.6. 
Correlative Studies 
Correlative studies may be proposed in the context of this clinical study and must include 
appropriate documentation, including ethics approval and subject informed consent prior to 
proceeding. In addition, investigators interested in conducting correlative studies must obtain the 
sponsor’s prior approval. Correlative studies will consider the impact on study data, if any, and 
priority will be given to samples defined in this protocol. Requests for correlative studies must be 
made in writing to the sponsor. 
15.7. 
Investigators and Study Personnel 
This study will be conducted by qualified investigators under the sponsorship of IMARA, Inc. at 
multiple study sites internationally. In relevant countries, all study staff members will receive 
and acknowledge a data processing notice. 
A CRO will be retained by the sponsor to implement and manage the study and is referred to in 
this protocol as the sponsor’s designee. 
The names of the CRO and the medical monitor, along with contact information (email 
addresses, telephone and fax numbers, etc.) of other contact persons at the CRO, will be listed in 
study-related documents retained at each study site. 
The names of study site staff trained for this study and their responsibilities must appear on the 
site delegation of authority log. 
A DMC will be established early in the study to monitor subject safety. The DMC will meet 
periodically as the study is ongoing to review the accumulating safety data and make 


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recommendations as necessary to the sponsor regarding ET of the study, continuation of the 
study, or modification of the study protocol as needed based on safety assessments. Additional 
details are provided in the DMC charter. 
15.8. 
Study Documentation, Record Keeping, and Retention of Documents 
The investigator has the responsibility to retain all study documents, including but not limited to 
the protocol, study site source documents, copies of eCRFs, IB, and regulatory documents (e.g., 
Form FDA 1572/Statement of Investigator, ICFs, and IRB/IEC correspondence) in accordance 
with Section 4.9 of the ICH E6(R2) GCP, US CFR 21 Part 312.62(c), and other regulatory and 
institutional requirements.  
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
study. 
The investigator/institution should maintain the study documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6[R2] Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Sponsor-specific essential documents (hard copy and electronic) should be retained by the 
investigator until at least 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH region or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational medicinal product. However, these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the sponsor. 
The study site should plan on retaining study documents per the study site contract. 
15.9. 
Audits and Inspections 
Upon request by representatives of national regulatory authorities, IRBs/IECs, or the sponsor or 
the sponsor’s designee, investigators and institutions involved in the clinical study will permit 
study-related monitoring, audits, and regulatory inspections, including direct access to source 
data and documents generated by this study. Audits and inspections may be conducted during the 
study or after its completion. If an audit or inspection is requested by parties other than sponsor, 
the investigator or designee must immediately inform the sponsor that a request has been made. 


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16. 
REFERENCES 
Akinsheye I, Alsultan A, Solovieff N, Ngo D, Baldwin CT, Sebastiani P, et al. Fetal 
haemoglobin in sickle cell anaemia. Blood. 2011 Jul 7;118(1):19-27. doi: 10.1182/blood-2011-
03-325258. Epub 2011 Apr 13. Review. PMID: 21490337. 
Alsultan A, Ngo D, Bae H, Sebastiani P, Baldwin CT, Melista E, et al. Genetic studies of foetal 
haemoglobin in the Arab-Indian haplotype sickle cell-β(0) thalassemia. Am J Hematol. 2013 
Jun;88(6):531-2. doi: 10.1002/ajh.23434. Epub 2013 May 2. 
Ballas, SK. The evolving pharmacotherapeutic landscape for the treatment of sickle cell disease. 
Mediterr J Hematol Infect Dis. 2020 Jan;12(1):e2020010. 
Barbosa CG, Aleluia AC, Pacheco AP, Paz SS, Zanette AM, Lyra IM, et al. Genetic modulation 
of HbF in Brazilians with HbSC disease and sickle cell anaemia. Am J Hematol. 2013 
Oct;88(10):923-4. doi: 10.1002/ajh.23538. Epub 2013 Sep 3. PMID: 2382843 
Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, et al. Effect of HU on the frequency 
of painful crises in sickle cell anaemia. Investigators of the Multicenter Study of Hydroxyurea in 
Sickle Cell Anemia. N Engl J Med. 1995;332(20):1317-22. 
Cokic VP, Smith RD, Beleslin-Cokic BB, Njoroge JM, Miller JL, Gladwin MT, et al. 
Hydroxyurea induces foetal haemoglobin by the nitric oxide-dependent activation of soluble 
guanylyl cyclase. J Clin Invest. 2003;111(2):231-9. 
Edwards R, Telfair J, Cecil H, Lenoci J. Reliability and validity of a self-efficacy instrument 
specific to SCD. Behav Res Ther. 2000 Sep;38(9):951-63. 
Erard F, Dean A, Schechter AN. Inhibitors of cell division reversibly modify haemoglobin 
concentration in human erythroleukemia K562 cells. Blood. 1981 Dec;58(6):1236-9. 
Fisher DA, Smith JF, Pillar JS, St Denis SH, Cheng JB. Isolation and characterization of 
PDE9A, a novel human cGMP-specific phosphodiesterase. J Biol Chem. 1998 Jun 
19;273(25):15559-64. 
Hanmer J, Dewitt B, Yu L, Tsevat J, Roberts M, Revicki D, et al. Cross-sectional validation of 
the PROMIS-Preference Scoring system. PLoS One. 2018 Jul;13(7):e0201093. 
Heeney MM, Ware RE. Hydroxyurea for children with sickle cell disease. Pediatr Clin North 
Am. 2008 Apr;55(2):483-501, x. doi: 10.1016/j.pcl.2008.02.003. Review. PMID: 18381097 
Hutson PH, Finger EN, Magliaro BC, Smith SM, Converso A, Sanderson PE, et al. The selective 
phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2 
ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4 
d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents. 
Neuropharmacology. 2011 Sep;61(4):665-76.  
Keller SD, Yang M, Treadwell MJ, Werner EM, Hassell KL. Patient reports of health outcome 
for adults living with sickle cell disease: development and testing of the ASCQ-Me item banks. 
Health Qual Life Outcomes. 2014 Aug;12:125. 
Lanzkron S, Carroll CP, Haywood C Jr. Mortality rates and age at death from sickle cell disease: 
U.S., 1979-2005. Public Health Rep. 2013 Mar-Apr;128(2):110-6. PMID: 23450875. 


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Matsumoto T, Kobayashi T, Kamata K. Phosphodiesterases in the vascular system. J Smooth 
Muscle Res. 2003;39(4):67–86. 
Nagasaki S, Nakano Y, Masuda M, Ono K, Miki Y, Shibahara Y, et al. Phosphodiesterase type 9 
(PDE9) in the human lower urinary tract: an immunohistochemical study. BJU Int. 2012 
Mar;109(6):934 40. 
Paulukonis ST, Eckman JR, Snyder AB, Hagar W, Feuchtbaum LB, Zhou M, Grant AM, 
Hulihan MM. Defining sickle cell disease mortality using a population-based surveillance 
system, 2004 through 2008. Public Health Rep. 2016 Mar-Apr;131(2):367-375. PMID: 
26957672. 
Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M, Temperley WH, Williams 
TN, Weatherall DJ, Hay SI. Global epidemiology of sickle haemoglobin in neonates: a 
contemporary geostatistical model-based map and population estimates. Lancet. 2013 Jan 
12;381(9861):142151. doi: 10.1016/S0140-6736(12)61229-X. Epub: 2012 Oct 25. 
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle 
cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639-
44. 
Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, Nathan DG. Hydroxyurea enhances foetal 
haemoglobin production in sickle cell anaemia. J Clin Invest. 1984 Aug;74(2):652-6. 
Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, et al. Pain in sickle 
cell disease — rates and risk factors. N Engl J Med. 1991; 325:11-16. DOI: 
10.1056/NEJM199107043250103. 
Schwam EM, Nicholas T, Chew R, Billing CB, Davidson W, Ambrose D, et al. A multicenter, 
double-blind, placebo-controlled trial of the PDE9A inhibitor, PF-04447943, in Alzheimer’s 
disease. Curr Alzheimer Res. 2014;11(5):413-21. 
Sheehan VA, Luo Z, Flanagan JM, Howard TA, Thompson BW, Wang WC, et al. Genetic 
modifiers of sickle cell anaemia in the BABY HUG cohort: influence on laboratory and clinical 
phenotypes. Am J Hematol. 2013 Jul;88(7):571-6. doi: 10.1002/ajh.23457. Epub 2013 May 30. 
van Staveren WC, Glick J, Markerink-van Ittersum M, Shimizu M, Beavo JA, et al. Cloning and 
localization of the cGMP-specific phosphodiesterase type 9 in the rat brain. J Neurocytol. 2002 
Sep-Nov;31(8-9):729-41. 
van der Staay FJ, Rutten K, Bärfacker L, Devry J, Erb C, Heckroth H, et al. The novel selective 
PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology. 
2008 Oct;55(5):908-18.


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17. 
APPENDICES  
17.1. 
Appendix 1: Lists of Potential In Vivo CYP3A Drug-Drug 
Interactions 
The list of in vivo CYP3A-sensitive substrates, inhibitors of CYP3A probes, inducers of CYP3A 
probes; list of in vivo inhibitors of P-gp probes; and list of in vivo inducers of CYP3A probes 
can be found online at, for instance, the following websites: 
 https://www.druginteractionsolutions.org 
 https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 
If there is any question as to whether a substance is permitted, the medical monitor and/or 
sponsor should be consulted. 


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17.2. 
Appendix 2: National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE, version 5.0) 
AEs will be graded according to NCI CTCAE, version 5.0. 
The NCI CTCAE criteria are available at the following web location: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 

SAP_001.pdf: 
Statistical Analysis Plan (SAP) 
Version Date: 01-March-2022   
 
Sponsor: Imara, Inc. 
 
Protocol no: IMR-SCD-301 
 
Page 1 of 67 
 
 
 Statistical Analysis Plan (SAP) 
Protocol Title: 
A Phase 2b Study to Evaluate the Safety and Efficacy of IMR-687 in 
Subjects with Sickle Cell Disease 
Protocol Version No./Date: 
5.0/5.1-UK/17-Feb-2022 
CRF Version No./Date: 
4.0/02-Jul-2021 
SAP Version No./Date: 
Final 1.0/01-Mar-2022 
 
 
 Approvals 
Sponsor 
Sponsor Name: 
Imara, Inc. 
Representative / Title: 
Constance Barysauskas, MS / Associate Director, Biostatistics 
Signature / Date: 
 
 
 
Representative / Title: 
Kenneth M. Attie, MD / Senior Vice President and Chief Medical Officer 
Signature / Date: 
 
 
 
Everest Clinical Research 
Biostatistician / Title: 
Francis Tang, M.Sc. / Associate Director, Statistical Operations 
Signature / Date: 
 
 
 
Review Biostatistician 
/ Title: 
Christine Kollar, M.Sc. / Principal Biostatistician 
Signature / Date: 
 
 
 
 
 
 


Statistical Analysis Plan (SAP) 
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Protocol no: IMR-SCD-301 
 
Page 2 of 67 
 Change History 
Version/Date 
Change Log 
Final 1.0/01-Mar-2022 
Created as new 
 
 
 


Statistical Analysis Plan (SAP) 
Version Date: 01-March-2022   
 
Sponsor: Imara, Inc. 
 
Protocol no: IMR-SCD-301 
 
Page 3 of 67 
 Table of Contents 
 
 Approvals ................................................................................................................................................ 1 
 Change History ....................................................................................................................................... 2 
 Table of Contents .................................................................................................................................... 3 
 Purpose ................................................................................................................................................... 5 
 Scope ...................................................................................................................................................... 5 
 Introduction ............................................................................................................................................. 5 
 Study Objectives ..................................................................................................................................... 5 
7.1 Primary Efficacy Objective ............................................................................................................... 5 
7.2 Primary Safety Objective ................................................................................................................. 5 
7.3 Secondary Efficacy Objectives ........................................................................................................ 5 
7.4 Secondary Pharmacokinetic Objective ............................................................................................ 6 
7.5 Exploratory Efficacy Objective ......................................................................................................... 6 
 Study Design ........................................................................................................................................... 6 
8.1 Sample Size and Power Considerations ......................................................................................... 8 
8.1.1 Sample Size Determination ................................................................................................... 8 
8.1.2 Power Estimation ................................................................................................................... 8 
8.2 Randomization ................................................................................................................................. 8 
 Study Endpoints, Variables and Covariates............................................................................................ 9 
9.1 Primary Efficacy Endpoint ................................................................................................................ 9 
9.2 Safety Endpoints .............................................................................................................................. 9 
9.3 Secondary Efficacy Endpoints ......................................................................................................... 9 
9.4 Secondary Pharmacokinetic Endpoint ........................................................................................... 10 
9.5 Exploratory Endpoints .................................................................................................................... 10 
 Conventions and Derivations .............................................................................................................. 11 
10.1 Method for Handling Missing Data ............................................................................................... 11 
10.2 Definitions of Baseline and Change from Baseline Values ......................................................... 11 
10.3 Definitions of Study Days ............................................................................................................. 11 
10.4 Definition of Treatment-Emergent Adverse Event ....................................................................... 12 
10.5 Windowing Conventions .............................................................................................................. 12 
 Analyses Sets ..................................................................................................................................... 14 
11.1 Safety Analysis Set ...................................................................................................................... 15 
11.2 PK Analysis Set ........................................................................................................................... 15 
11.3 PK Evaluable Set ......................................................................................................................... 16 
11.4 Intent-to-Treat Analysis Set ......................................................................................................... 16 
11.5 Modified Intent-to-Treat Analysis Set ........................................................................................... 16 
11.6 Per Protocol Analysis Set ............................................................................................................ 16 
 Overview of Planned Analyses ........................................................................................................... 16 
12.1 Hypothesis Testing ...................................................................................................................... 17 
12.2 Multiple Comparisons and Control of Type I Error ...................................................................... 17 
12.3 Interim Analysis ............................................................................................................................ 18 
12.4 Final Analysis ............................................................................................................................... 20 
12.5 Data Monitoring Committee ......................................................................................................... 21 
 Statistical Methods .............................................................................................................................. 22 
13.1 Subject Disposition ...................................................................................................................... 22 
13.2 Important Protocol Deviations ...................................................................................................... 23 
13.3 Exposure and Drug Accountability ............................................................................................... 23 
13.4 Demographic and Baseline Characteristics ................................................................................. 24 
13.4.1 Medical and Surgical history .............................................................................................. 25 
13.4.2 Prior and Concomitant Medications ................................................................................... 25 


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13.4.3 Concomitant Procedures ................................................................................................... 25 
13.5 Endpoint Analyses ....................................................................................................................... 25 
13.5.1 Summary of Analyses ........................................................................................................ 25 
13.5.2 Primary Efficacy Analysis .................................................................................................. 27 
13.5.3 Subgroup analyses will be performed as supplementary analyses and detailed in Section 
13.5.6.Key Secondary Efficacy Analysis ...................................................................................... 31 
13.5.4 Other Secondary Endpoints .............................................................................................. 33 
13.5.5 Exploratory Efficacy Endpoints .......................................................................................... 37 
13.5.6 Subgroup Analyses ............................................................................................................ 38 
13.5.7 Multiplicity Adjustment ....................................................................................................... 39 
13.5.8 Safety Analyses ................................................................................................................. 39 
13.5.9 Pharmacokinetic Endpoints ............................................................................................... 44 
 References .......................................................................................................................................... 48 
 Glossary of Abbreviations ................................................................................................................... 49 
 Appendices ......................................................................................................................................... 51 
Appendix 1 ACSQ-Me Scoring Tables ........................................................................................................ 51 
Appendix 2 PROMIS-29+2 Profile v2.1 (PROPr) Scoring Tables .............................................................. 52 
Appendix 3 Schedule of Assessments ........................................................................................................ 54 
Appendix 4 Data Handling Rules ................................................................................................................ 57 
Appendix 5 CTCAE Grade Criteria for Selected Hematology and Chemistry parameters ......................... 60 
Appendix 6 SAS Codes for Statistical Analysis .......................................................................................... 65 
Appendix 7 Power Calculation for the Primary Endpoint (Annualized Rate of VOCs) ............................... 67 
Appendix 8 Mock-up Tables, Listings, and Figures .................................................................................... 67 
 


Statistical Analysis Plan (SAP) 
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Protocol no: IMR-SCD-301 
 
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 Purpose 
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Imara Protocol IMR-SCD-301. 
 Scope 
The Statistical Analysis Plan outlines the following: 
• 
Study Objectives 
• 
Study Design 
• 
Applicable Study Definitions 
• 
Statistical Methods 
 Introduction 
This SAP should be read in conjunction with the study protocol and case report form (CRF). Any further 
changes to the protocol or CRF may necessitate updates to the SAP prior to database lock. If the SAP 
and the final protocol are different, the SAP prevails. 
 Study Objectives 
7.1 Primary Efficacy Objective 
• 
To evaluate the effect of IMR-687 versus placebo on the annualized rate of vaso-occlusive crises 
(VOCs) 
7.2 Primary Safety Objective 
• 
To evaluate the safety and tolerability of IMR-687 versus placebo. 
7.3 Secondary Efficacy Objectives 
The key secondary efficacy objective is: 
• 
To evaluate effect of IMR-687 versus placebo on the time to the first occurrence of a vaso-
occlusive crisis 
• 
To evaluate the fetal hemoglobin (HbF) response to IMR-687 versus placebo 
The other secondary efficacy objectives are: 
• 
To evaluate the effect of IMR-687 versus placebo on other measures of vaso-occlusive crises 
(VOCs) 
• 
To evaluate the effect of IMR-687 versus placebo on percentage of cells positive for HbF (% F-
cells) and total hemoglobin (Hb) 
• 
To evaluate the effect of IMR-687 versus placebo on biomarkers of red blood cell (RBC) 
hemolysis 
• 
To evaluate the effect of IMR-687 versus placebo on quality of life (QoL) measures 
• 
To evaluate the effect of IMR-687 versus placebo on biomarkers of adhesion, inflammation, and 
cardiac stress and on RBC indices 


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7.4 Secondary Pharmacokinetic Objective 
The secondary pharmacokinetic (PK) objective is: 
• 
To evaluate the pharmacokinetic (PK) exposure of IMR-687 
7.5 Exploratory Efficacy Objective 
The exploratory objective is to evaluate the effect of IMR-687 versus placebo on renal function 
 Study Design 
This is a Phase 2b, randomized, double-blind, placebo-controlled, multicenter study of subjects aged 18 
to 65 years with sickle cell disease (SCD; homozygous sickle hemoglobin [HbSS], sickle-β0 [HbSβ0] 
thalassemia, or sickle-β+ [HbSβ+] thalassemia) to evaluate the safety and efficacy of the 
phosphodiesterase type 9 inhibitor, IMR-687, administered once daily (QD) for 52 weeks. This study will 
enroll approximately 99 subjects with SCD. This study consists of a screening period (up to 4 weeks), a 
double-blind treatment period (52 weeks), and a safety follow-up period (4 weeks). 
The study schematic is provided in Figure 1 below, and the schedule of assessments is provided in 
Appendix 3 of this document. 
Subjects will receive either IMR-687 (lower dose or higher dose) or placebo in a blinded fashion. IMR-687 
will be supplied as 100, 150, or 200 mg white tablets. Placebo and the different doses of IMR-687 are 
visually identical. Subjects will be advised to take 2 tablets orally, once daily (QD). Prior to the Protocol 
version 4.0, lower dose was defined as an exposure of ≥3.0 to ≤4.5 mg/kg, subjects in the lower dose 
group weighing <67 kg will be dispensed 100 mg tablets and those weighing ≥67 kg will be dispensed 
150 mg tablets. Higher dose was defined as an exposure of >4.5 to ≤6.7 mg/kg, subjects in the higher 
dose group weighing <67 kg will be dispensed 150 mg tablets and those weighing ≥67 kg will be 
dispensed 200 mg tablets. In Protocol version 4.0 and later, lower dose was defined as an exposure of 
≥3.4 to ≤5.0 mg/kg, subjects in the lower dose group weighing <60 kg will be dispensed 100 mg tablets 
and those weighing ≥60 kg will be dispensed 150 mg tablets. Higher dose was defined as an exposure of 
>5.0 to ≤6.7 mg/kg, subjects in the higher dose group weighing <60 kg will be dispensed 150 mg tablets 
and those weighing ≥60 kg will be dispensed 200 mg tablets. 
Initially, subjects will be randomly assigned in a 2:1 ratio to receive either IMR-687 lower dose or placebo. 
Prior to the introduction of IMR-687 higher dose, the Data Monitoring Committee (DMC) will review safety 
data for at least 5 subjects who received IMR-687. If the DMC recommends inclusion of the higher dose, 
randomization will then proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose, or placebo). 
During study conduct under Protocol Version 3.0, the DMC approved opening of enrollment to the higher 
dose IMR-687 group, enrollment to the higher dose went into effect on 12 March 2021. 
Subjects may or may not be concomitantly receiving a stable dose of hydroxyurea (HU) according to the 
subject’s established treatment plan. Randomization will be stratified by use of HU (yes vs. no) and by 
region (North America/Europe vs. Africa/Middle East). 
Subjects will be directed to take study drug (either IMR-687 or placebo) with food, but if a subject does 
not do so, it will not be considered a protocol deviation. 
An interim analysis (IA) will be conducted when all subjects have completed study assessments 
(including VOC incidence) at Week 24 or terminated the study early. The IA will be a partial unblinding 
event with corresponding alpha spending strategies to manage Type 1 error. 
A final analysis (FA) will be conducted at study completion (i.e., when all subjects have reached Week 56 
or terminated early), following database lock and unblinding. Alpha available at the final analysis will be 
propagated based on the alpha spent from the IA. 


Statistical Analysis Plan (SAP) 
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Figure 1: Overview of Study Design and Dose Groups 
 
 
 
 


Statistical Analysis Plan (SAP) 
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Protocol no: IMR-SCD-301 
 
 
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8.1 Sample Size and Power Considerations 
8.1.1 Sample Size Determination 
The sample size of this study was originally determined based on HbF responder rate as the primary 
endpoint: 
Assuming a 5% HbF response rate for placebo, the study having approximately 31 placebo and 49 higher 
dose subjects would have > 85% power to detect a targeted difference of 30%, using a Chi-square test 
for comparison of proportions (with continuity-correction) and a two-sided alpha of 0.050. The assumed 
responder rate for placebo (5%) and highest tolerated dose subjects (>35%) includes the dropout 
subjects (regarded as are non-responders at Week 24).  
Based on FDA feedback a new primary endpoint was adopted with a corresponding change in statistical 
methodology as specified in Section 8.1.2 below. 
As of completion of this SAP, enrollment was completed in the ongoing study, with a total of 115 subjects 
randomized between August 2020 and August 2021. Out of the 115 subjects, the first 17 subjects were 
randomized in a 2:1 ratio to Lower Dose: Placebo, and the remaining 98 subjects proceeded with 
randomization in a 1:2:1 ratio for Lower Dose: Higher Dose: Placebo.  
8.1.2 Power Estimation  
Annualized rate of VOCs was changed from a key secondary endpoint in Protocol 4.0/4.1 (April 2021) to 
the primary efficacy endpoint in this SAP and in Protocol Amendment 5.0/5.1 (February 2022). The power 
calculation below was based on the projection that there will be approximately 49 randomized subjects in 
higher dose, 35 subjects in lower dose and 31 subjects in placebo group. 
Assuming that the actual data distribution is normal when the significance level (alpha) of the test is 
0.050, the standard deviation is 2.7 in both groups, and there are no dropouts, there will be 88% power to 
detect a difference between the medians of 5.0 and 3.0 for the placebo and the IMR-687 highest tolerated 
dose groups, respectively (i.e., a 40% difference), using a two-sided Wilcoxon Rank-Sum test (Table 1). 
Assuming a 25% dropout rate, the power will be 78%. 
Table 1 Power Estimation 
Scenarios  
N for 
IMR-687 
Highest 
Tolerated 
Dose 
 
N for 
 Placebo 
Significance 
Level (two-
sided alpha) 
Standard 
Deviation 
Difference 
Power 
No Dropout 
49 
31 
0.05 
2.7 
40% 
88% 
With 25% 
Dropout 
Rate* 
37 
24 
0.05 
2.7 
40% 
78% 
* estimated based on Ataga et al. 
 
The power calculation for the Annualized rate of VOCs was carried out in PASS Version 2020 v20.0.3. 
See Appendix 7 for details.  
8.2 Randomization 
All subjects who are screened (including screen failures) will be assigned a unique subject identification 
number. 
On Day 1, eligible subjects will be assigned another unique number (randomization number) in sequential 
order. The randomization number codes the subject’s initial treatment assignment according to the 


Statistical Analysis Plan (SAP) 
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Page 9 of 67 
randomization schedule generated prior to the study. Randomization will follow a permuted block design 
and will be stratified by use of HU (yes vs. no) and by region (North America/Europe vs. Africa/Middle 
East). Initially, subjects will be randomly assigned in a 2:1 ratio using a block size of 6 to receive either 
IMR-687 lower dose or placebo respectively. If the DMC recommends inclusion of the higher dose, 
randomization will then proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose, or placebo) 
using a block size of 4. 
Randomization numbers will not be re-used once assigned. If a subject is replaced, the replacement 
subject will receive the same treatment assignment as the replaced subject, and a different leading 
number will be used for the replacement randomization number.  
Randomization schedules were generated by Cytel, a subcontractor of the interactive voice/web response 
system (IXRS) vendor Suvoda. 
 Study Endpoints, Variables and Covariates 
9.1 Primary Efficacy Endpoint 
The primary endpoint is the annualized rate of VOCs  
9.2 Safety Endpoints 
Safety endpoints include the number and percentage of subjects with the following:  
• 
At least one treatment-emergent adverse events (AEs) 
• 
At least one treatment-emergent serious adverse events (SAEs) 
• 
At least one clinically significant change in a laboratory test parameter 
• 
At least one clinically significant change in a vital signs parameter 
• 
At least one clinically significant change in an electrocardiogram (ECG) parameter 
9.3 Secondary Efficacy Endpoints 
• 
Key secondary efficacy endpoint 1: Time to first VOC  
• 
Key secondary efficacy endpoint 2: Proportion of HbF responders (defined as proportion of 
subjects with an absolute increase of ≥3% in HbF from baseline) at Week 24 
• 
The study has the following additional secondary endpoints: 
o 
Proportion of VOC-free subjects  
o 
Annualized rate of VOC-related hospitalizations  
o 
Annualized rate of days hospitalized for VOC-related hospitalizations  
o 
Time to second VOC 
o 
Proportion of HbF responders (defined as proportion of subjects with an absolute 
increase of ≥3% in HbF from baseline) at Week 52 
o 
Proportion of Hb responders (defined as proportion of subjects with an absolute increase 
of ≥1.0 g/dL in total Hb from baseline) at Week 24 and Week 52 
o 
Change from baseline in the following at Weeks 24 and 52: 
 
HbF (%), F-cells (%), total Hb (g/dL)  
 
Biomarkers of red blood cell (RBC) hemolysis (% and absolute reticulocytes, 
unconjugated [indirect] bilirubin, and lactate dehydrogenase (LDH))  


Statistical Analysis Plan (SAP) 
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 
Each measured subdomain of the Adult Sickle Cell Quality of Life Measurement 
Information System (ASCQ-Me) questionnaire  
 
Total preference score and individual domain scores of the Patient-Reported 
Outcomes Measurements Information System – Preference (PROMIS 29 + 2 
Profile v2.1 [PROPr]) questionnaire  
 
Overall score of the Sickle Cell Self-Efficacy Scale (SCSES)  
 
Change from baseline in biomarkers of adhesion including soluble E-selectin 
(E-sel), P-selectin (P-sel), intercellular adhesion molecule 1 (ICAM-1), and 
vascular cell adhesion molecule 1 (VCAM-1) at Week 24 and Week 52 
 
Biomarkers of inflammation such as high-sensitivity C reactive protein (hsCRP) 
and myeloperoxidase [MPO] 
 
Biomarkers of cardiac stress such as N-terminal prohormone of brain natriuretic 
peptide (NT-proBNP)  
 
RBC indices, such as mean corpuscular volume (MCV) 
9.4 Secondary Pharmacokinetic Endpoint 
PK will be assessed for IMR-687 (where feasible) 
• 
PK profile (concentration-time measurements) and population PK of IMR-687 
9.5 Exploratory Endpoints 
• 
Renal Function 
o 
Change from baseline in renal function as measured by the urine protein-to-creatinine 
(Pr:Cr) ratio, microalbumin, and urine Cystatin Cat Week 24 and Week 52 
• 
VOCs:  
o 
Number and percentage of subjects with at least 1 VOC event 
o 
Number and percentage of subjects by category of number of VOC events: 0, 1, 2-4, 5-7, 
8-12, 13+ 
o 
Number of and percentage of subjects with at least one VOC event lasting for ≥ 48 hours 
o 
Number and percentage of subjects with complicated VOCs (ACS, priapism, hepatic or 
splenic sequestration) 
 
Number and percentage of subjects with at least 1 ACS 
 
Number and percentage of males with priapism 
 
Number and percentage of subjects with hepatic or splenic sequestration 
o 
Number of and percentage of subjects with uncomplicated VOCs 
o 
Time to first event of complicated VOCs 
o 
Annualized rate of days of VOCs (in days) 
o 
Annualized rate of VOCs, excluding subjects with a short period of exposure (e.g. <4 
weeks) 
o 
Annualized rate of uncomplicated VOCs  


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• 
VOC-Related Hospitalizations: 
o 
Number and percentage of subjects with at least 1 VOC-related hospitalization 
o 
Number and percentage of subjects by category of number of VOC-related 
hospitalizations: 0, 1, 2-4, 5-7, 8-12, 13+ 
• 
RBC Transfusions: 
o 
Time to first RBC transfusion  
o 
Number and percentage of subjects with at least 1 RBC Transfusion 
• 
Relationships between VOC and PD parameters 
o 
Correlation of annualized rate of VOCs and PD parameters (e.g., HbF, Hb and F-cells) 
with each other, at Week 24 and Week 52, for HU and non-HU use subgroups separately 
and together 
 Conventions and Derivations 
10.1 Method for Handling Missing Data 
There will be no imputation of incomplete or missing data unless specified otherwise in this SAP. 
Please refer to Appendix 4 for specific data handling rules, including missing last dose date for IA, 
incomplete/missing dates for adverse events and prior/concomitant medications, interpretation of non-
numeric results (e.g. “< BLQ”, “>x.xx”) from PK and laboratory measures, etc. 
Efficacy and PK imputation for missing data will be detailed in Section 13.5. 
Imputation will be noted in the footnotes. The original values/results will be presented in the data listings.  
10.2 Definitions of Baseline and Change from Baseline Values 
Unless otherwise specified, baseline is defined as the last non-missing measurement prior to the first 
dose of study drug.  
All ECG assessments at a visit are to be performed in triplicate at each scheduled visit. The baseline 
value for ECG parameters will be derived as the average of all non-missing values, at the last visit prior to 
the first dose of study drug. Post-baseline assessments at a visit will be averaged for analysis. 
In analyses of pharmacodynamics (PD) parameters, baseline is defined as the average of non-missing 
values from the screening and baseline visits. PD assessments include the following laboratory 
measurements based on blood samples (HbF-associated biomarkers and total Hb; biomarkers of RBC 
hemolysis, adhesion, inflammation, and cardiac stress; RBC indices). 
Change from baseline at a post-baseline visit is defined as follows: 
• 
For the ECG parameters: Post-Baseline Average Value – Baseline Average Value 
• 
For PD parameters:  Post-Baseline Value – Baseline Average Value 
• 
For all other parameters: Post-Baseline Value – Baseline Value 
10.3 Definitions of Study Days 
Study Day 1 is defined as the date on which subjects are administered their first dose of study drug. For 
visits or events that occur on or after the first dose of study drug, study day is defined as (date of visit 
[event] – date of first dose of study drug + 1). For visits (or events) that occur prior to Study Day 1, study 
day is defined as (date of visit [event] – date of first dose of study drug). There is no Study Day 0. 


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10.4 Definition of Treatment-Emergent Adverse Event 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges on or after initiation of 
study drug, or an AE that existed pre-treatment and worsened in severity on or after initiation of study 
drug, through 30 days after the last dose of study drug. 
10.5 Windowing Conventions  
All scheduled study visits are defined relative to Study Day 1, the date of first dose. Scheduled visit 
windows are defined in Appendix 3. A windowing convention will be used to determine the analysis visit 
value for a given measurement and will be applicable for all by-visit summaries and analyses for efficacy 
and safety data. Refer to Table 2 below for specific visit windows. 


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Table 2 Visit Windows for Efficacy and Safety Analyses  
For all Efficacy (Except for QoL) and PD Analyses 
Scheduled Study Visit 
(Protocol Scheduled Day) 
Analysis Visit Window 
(Study Day) 
Baseline 
≤ 1 
Week 4 (Day 28 ± 5) 
2 to 43 
Week 8 (Day 56 ± 5) 
44 to 71 
Week 12 (Day 84 ± 5) 
72 to 99 
Week 16 (Day 112 ± 7) 
100 to 141 
Week 24 (Day 168 ± 7) 
142 to 211 
Week 36 (Day 252 ± 7) 
212 to 309 
Week 52 (Day 364 ± 7) 
≥ 310 
For QoL Analysis 
Scheduled Study Visit 
(Protocol Scheduled Day) 
Analysis Visit Window 
(Study Day) 
Baseline 
≤ 1 
Week 4 (Day 28 ± 5) 
2 to 57 
Week 12 (Day 84 ± 5) 
58 to 127 
Week 24 (Day 168 ± 7) 
128 to 211 
Week 36 (Day 252 ± 7) 
212 to 309 
Week 52 (Day 364 ± 7) 
≥ 310 
For Safety Analysis 
Scheduled Study Visit 
(Protocol Scheduled Day) 
Analysis Visit Window 
(Study Day) 
Baseline 
≤ 1 
Week 1 (Day 7 ± 2)  
2 to 15 
Week 4 (Day 28 ± 5) 
16 to 43 
Week 8 (Day 56 ± 5) 
44 to 71 
Week 12 (Day 84 ± 5) 
72 to 99 
Week 16 (Day 112 ± 7) 
100 to 127 
Week 20 (Day 140 ± 7) 
128 to 155 
Week 24 (Day 168 ± 7) 
156 to 190 
Week 30 (Day 210 ± 7) 
191 to 232 
Week 36 (Day 252 ± 7) 
233 to 274 
Week 44 (Day 308 ± 7) 
275 to 337 


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For Safety Analysis 
Scheduled Study Visit 
(Protocol Scheduled Day) 
Analysis Visit Window 
(Study Day) 
Week 52 (Day 364 ± 7) 
338 to 379 
Week 56 (Day 392 ± 7) 
≥ 380 
 
Windowing will be applied prior to any missing data calculations. The last non-missing measurement 
taken prior to the date of first dose (including unscheduled assessments) will be labeled as “Baseline”. 
Unscheduled or Screening visits that occurred before the baseline visit will not be assigned an analysis 
visit. The early discontinuation visit will be eligible for allocation to an analysis visit.  
If one or more results for a variable are assigned to the same analysis visit, the result with the date 
closest to the scheduled day per protocol will be used in the analysis. If 2 measurements in the same 
analysis visit window are equidistant from the scheduled study day, the earliest measurement will be used 
in the analysis. If multiple assessments are available on the same day (for the same time point), then the 
average of the assessment will be used in the analysis. If both central and local assessments of the same 
lab test are available on the same day, the central result will take precedence over the local result. 
 Analyses Sets 
All analysis sets will include only subjects who gave informed consent and are summarized in Table 3. 


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Table 3 Analysis Sets and Definitions 
Analysis Set 
Definition 
Use 
How Analyzed 
Safety 
All subjects who have received 
any amount of study drug  
Safety and 
tolerability 
According to actual 
treatment received 
PK (Analysis) 
All subjects in the Safety 
Analysis Set who have 
received at least 1 dose of 
IMR-687 and have any 
measurable post-dose IMR-
687 concentration-time data  
PK concentrations 
According to actual 
treatment received 
PK 
(Evaluable) 
All subjects in the Safety 
Analysis Set who have 
received at least 1 dose of 
IMR-687 and have at least 4 
consecutive non-zero post-
dose IMR-687 concentration-
time data points. 
PK parameters 
According to actual 
treatment received 
ITT 
All randomized subjects  
Efficacy/PD  
According to randomized 
treatment assigned 
mITT 
All randomized subjects who 
had at least 1 VOC in the 12 
months prior to randomization 
and have received at least one 
dose of study drug 
Efficacy/PD  
According to randomized 
treatment assigned 
Per Protocol 
(PP) 
All subjects in the Safety 
Analysis Set who had at least 1 
VOC in the 12 months prior to 
randomization, completed at 
least 1 valid clinical outcomes 
assessment without major 
protocol deviations or events 
that would be expected to 
affect the analysis and did not 
discontinue prior to Week 24 
for reasons other than AEs 
Efficacy/PD  
According to actual 
treatment received 
11.1 Safety Analysis Set 
The safety analysis set will include all subjects who have received any amount of study drug and from 
whom informed consent has been obtained. The safety analysis set will be used to summarize all safety 
and tolerability data. In safety data summaries, subjects will be analyzed according to the actual 
treatment they received. 
11.2 PK Analysis Set 
The PK Analysis Set, will be defined as a subset of the Safety Analysis Set who are randomized, have 
received at least 1 dose of IMR-687, and have any measurable post-dose IMR-687 concentration-time 
data This set will be used to generate the corresponding PK concentration summaries and plots. 


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11.3 PK Evaluable Set 
The PK Evaluable Set will be defined as all subjects in the Safety Analysis Set who are randomized, have 
received at least 1 dose of IMR-687, and have at least 4 consecutive non-zero post-dose IMR-687 
concentration-time data points. The PK Evaluable Set will be used to generate the corresponding PK 
exposure (parameter) assessments. 
11.4 Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all randomized subjects. The ITT set will be used as the 
primary analysis set to summarize efficacy, PD, and clinical outcome parameters. Subjects will be 
analyzed according to their randomized treatment assignment. 
11.5 Modified Intent-to-Treat Analysis Set 
The modified intent-to-treat (mITT) analysis set will include all randomized subjects who had at least 1 
VOC in the 12 months prior to randomization and have received at least one dose of study drug. The 
mITT set will be used for sensitivity analyses of efficacy, PD, and clinical outcome parameters. Subjects 
will be analyzed according to their randomized treatment assignment. 
11.6 Per Protocol Analysis Set 
The per protocol (PP) analysis set will include all subjects in the safety analysis set who had at least 1 
VOC in the 12 months prior to randomization, completed at least 1 valid clinical outcomes assessment 
without major protocol deviations or events that would be expected to affect the analysis and did not 
discontinue prior to Week 24 for reasons other than AEs. Subjects will be analyzed according to the 
actual treatment they received. The PP set will be used for sensitivity analyses of efficacy, PD, and 
clinical outcome parameters.  
Major protocol deviations and subjects (or data) excluded from the PP Analysis Set will be defined by the 
Sponsor in a blinded manner prior to database lock. 
 Overview of Planned Analyses 
This section summarizes the planned analyses for efficacy, PD, PK and safety for the interim analysis (IA) 
and final analysis (FA). The statistical analyses, which will be performed on locked and cleaned data 
extracts, will include all data through protocol-specified analysis time points. The data cut-off for the IA 
are specified below. The DMC may recommend the discontinuation of a dose arm, due to safety, which 
will inform the highest tolerated dose. Selected personnel involved in the analysis and review of unblinded 
data for the IA will abstain from attending study conduct and operational meetings after the data has been 
unblinded for any reason. Detailed statistical methods are defined in Section 13.0.  
An IA will be performed after all subjects have reached Week 24 or terminated early. The FA will be 
performed after all subjects have completed the study. The critical significance levels for the IA and FA to 
maintain an overall two-sided type I error rate of 5% will be based on an O’Brien-Fleming boundary, 
calculated from a Lan-DeMets alpha spending function, based on the number of highest tolerated dose 
and placebo subjects used in the primary efficacy analysis in the ITT analysis set.  
A summary of planned analysis for IA/FA are summarized in Table 4 below.   


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Table 4 Planned Analyses for IA and FA 
 
IA 
FA 
Disposition, Baseline and Disease 
Characteristics 
Yes 
Yes 
Exposure 
Yes 
Yes 
Concomitant and Prior Medications 
 
Yes 
Primary Efficacy: Annualized Rate of 
VOCs  
Yes, with Alpha spending -
fixed sequence design [a] 
Yes, with propagated Alpha 
from IA [a] 
Key Secondary Efficacy: Time to first 
VOC and HbF Responder rate at 
Week 24 
Yes [b] 
Yes [b] 
Other Secondary Efficacy: Biomarkers 
and Specialty Hematology parameters 
 
Yes  
Other Secondary Efficacy (Annualized 
rate of VOC-related hospitalizations, 
etc.)  
 
Yes  
Other Secondary Efficacy: PROs 
(ASCQ-Me, PROPr, SCSES) 
 
Yes 
Exploratory Efficacy 
 
Yes 
Subgroup Analysis 
 
Yes 
Safety (AEs, Laboratory, Vital Signs, 
ECGs, etc.) 
Yes, selected  
outputs only 
Yes 
PK 
Yes, selected  
outputs for plasma 
concentration only 
Yes 
[a] Two-sided alpha spending at IA for primary efficacy analysis is 0.002. Propagated Alpha of 0.0494 is to be spent at FA. 
[b] Statistical testing for key secondary efficacy will proceed only after the efficacy of the primary efficacy endpoint is 
demonstrated.  
12.1 Hypothesis Testing 
For the primary comparisons, the null hypothesis for each pairwise comparison will be that the treatment 
effect of the highest tolerated dose of IMR-687 is equal to that of placebo; the alternative hypothesis is 
then that the treatment effect of the highest tolerated dose of IMR-687 and that of placebo are not equal.  
P-values will thus be reported as two-sided.  
Key secondary and other secondary efficacy analyses will involve the above hypothesis applied to the 
secondary efficacy endpoints. 
12.2 Multiple Comparisons and Control of Type I Error  
An IA will be performed after all subjects have reached Week 24 or terminated early. The FA will be 
performed after all subjects have completed the study at Week 52. As Figure 2 shows, a fixed sequence 
hierarchical testing strategy will be used to control the Type I error rate across planned analyses (IA/FA) 
for all efficacy analyses. An O’Brien-Fleming boundary, calculated from a Lan-DeMets alpha spending 
function, will be used to control the alpha spending for the primary comparison at IA. The details of alpha 


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spending and the order of testing of the other secondary endpoints are summarized in Sections 12.3 and 
Section 12.4.  
Figure 2: Two-sided Alpha Available for Spending in the Fixed Sequence 
Hierarchical Testing Procedure 
 
 
12.3 Interim Analysis 
The study will have one unblinded (partial) interim analysis (IA). An unblinded statistical team from Everest 
will perform the analyses. The IA will be based on the ITT analysis set. 
To facilitate the IA, certain sponsor representatives and designees may be unblinded to individual treatment 
assignments prior to and during the IA (including the unblinded clinical research organization (CRO) 
biostatistician and external groups for bioanalytical, PK, and PK/PD analyses). Details are provided in the 
study unblinding plan. The blinded Sponsor and CRO study team members will be unblinded solely to the 
group analysis results (but not individual subject results) at the conclusion of the IA. 
The IA will be performed after all subjects have reached Week 24 or terminated early. The IA will include 
summaries of disposition, baseline demographics and disease characteristics, safety analysis (summary of 
adverse events, change from baseline for laboratory [excluding specialty hematology], vital sign and 12-
lead ECG parameters), as well as analyses of the efficacy endpoints.   
At the IA, all the efficacy endpoints will be tested in a hierarchical order, at the highest tolerated dose of 
IMR-687 vs placebo. If all the efficacy comparisons are successful, testing of the IMR-687 pooled dose 
vs. placebo, and of lower dose vs. placebo will be performed. If the first comparison fails (i.e. the null 
hypothesis is not rejected), the statistical analysis and the p-values from all remaining comparisons will 
Interim Analysis with Alpha 
Spending=0.002
Primary Efficacy Testing: 
Annualized Rate of VOCs
Key Secondary Testing: Time 
to First VOC
Key Secondary Testing:  HbF 
Responder at Week 24
Other Secondary Endpoints
Final Analysis with 
Propagated Alpha=0.0494 
Primary Efficacy Testing: 
Annualized Rate of VOCs
Key Secondary Testing: Time 
to First VOC
Key Secondary Testing:  HbF 
Responder at Week 24
Other Secondary Endpoints
Sequential Testing Gatekeeping Process 


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not be reported at the interim analysis. The hierarchical order of testing of primary, key secondary and 
other secondary endpoints is: 
1. 
Annualized rate of VOCs 
2. 
Time to first VOC 
3. 
HbF responder rate at Week 24 
4. 
Proportion of VOC-free subjects  
5. 
Annualized rate of VOC-related hospitalization 
6. 
Annualized rate of days hospitalized for VOC-related hospitalizations 
7. 
Time to second VOC 
8. 
Change from baseline in key biomarkers of RBC hemolysis (indirect bilirubin and % reticulocytes) 
at Week 24  
9. 
Change from baseline in HbF (%) and F-cells (%) at Week 24  
10. Hb responder rates at Week 24  
11. Change from baseline in total Hb (g/dL) at Week 24  
12. Change from baseline in other biomarkers of RBC hemolysis (absolute reticulocytes and lactate 
dehydrogenase [LDH]) at Week 24  
13. Change from baseline in biomarkers of adhesion such as soluble E-selectin (E-sel), P-selectin (P-
sel), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) 
at Week 24  
14. Change from baseline in biomarkers of inflammation such as high-sensitivity C-reactive protein 
(hsCRP) and myeloperoxidase (MPO) at Week 24  
15. Change from baseline in biomarkers of cardiac stress such as N-terminal prohormone of brain 
natriuretic peptide (NT-proBNP) at Week 24  
16. Change from baseline in RBC indices, such as mean corpuscular volume (MCV) at Week 24  
17. Change from baseline in each measured subdomain of ASCQ-Me questionnaire at Week 24  
18. Change from baseline in total preference score and individual domain scores of PROPr 
questionnaire at Week 24  
19. Change from baseline in overall score of the Sickle Cell Self-Efficacy Scale (SCSES) at Week 24  
The primary efficacy endpoint (annualized rate of VOCs) will be tested using a stratified Wilcoxon rank-
sum test. The annualized rate of VOCs will be based on the data collected once all subjects have 
reached Week 24. Based on the proportion of information available at the IA (24 weeks at IA/52 weeks at 
FA = 0.4615), the alpha spending and O’Brien-Fleming boundaries as implemented by a Lan-DeMets 
alpha spending function will be as shown in Table 5 below. The lower bound of O’Brian-Fleming boundary 
will be used as the critical value to test the primary endpoint at the highest tolerated IMR-687 dose. If the 
p-value from the primary comparison is equal or below the critical value at the IA, the success of the 
primary efficacy analysis can be claimed. If not, the comparison will be re-done at the FA, when the 
information from the whole study is available, using a propagated alpha (also shown in Table 5).  
 


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Table 5 Alpha Spending Summary 
Analysis 
One-sided Nominal 
p-Value 
(Lower Bound of 
O’Brien-Fleming 
Boundary) 
Two-sided Nominal 
p-Value 
 
Lower Bound Alpha 
Spending 
Interim Analysis 
0.0010 
0.0020 
0.001 
Final Analysis 
0.0247 
0.0494 
0.024 
Total 
 
 
0.025 
12.4 Final Analysis 
The database will be locked prior to the final analysis (FA) which will be conducted when all randomized 
subjects have reached Week 56 or terminated early. As described in Section 12.3, all the efficacy endpoints 
will be tested in a hierarchical order, at the highest tolerated dose of IMR-687 vs placebo. If all the efficacy 
comparisons are successful, testing of the IMR-687 pooled dose vs. placebo, and of lower dose vs. placebo 
will be performed. Propagated alpha from the primary efficacy analysis at the IA will be used in the FA to 
maintain an overall type I error rate of 5% for 2-sided testing. After the first instance of a failure to reject the 
null hypothesis, p-values from all remaining comparisons will still be reported, but deemed nominal. The 
hierarchical order of testing of primary, key secondary and other secondary endpoints is: 
1. 
Annualized rate of VOCs 
2. 
Time to first VOC 
3. 
HbF responder rate at Week 24 
4. 
Proportion of VOC-free subjects  
5. 
Annualized rate of VOC-related hospitalization 
6. 
Annualized rate of days hospitalized for VOC-related hospitalizations 
7. 
Time to second VOC 
8. 
Change from baseline in key biomarkers of RBC hemolysis (indirect bilirubin and % reticulocytes) 
at Week 24 and Week 52  
9. 
HbF responder rate at Week 52  
10. Change from baseline in HbF (%) and F-cells (%) at Week 24 and Week 52  
11. Hb responder rates at Week 24 and Week 52  
12. Change from baseline in total Hb (g/dL) at Week 24 and Week 52  
13. Change from baseline in other biomarkers of RBC hemolysis (absolute reticulocytes and lactate 
dehydrogenase [LDH]) at Week 24 and Week 52 
14. Change from baseline in biomarkers of adhesion such as soluble E-selectin (E-sel), P-selectin (P-
sel), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) 
at Week 24 and Week 52  
15. Change from baseline in biomarkers of inflammation such as high-sensitivity C-reactive protein 
(hsCRP) and myeloperoxidase (MPO) at Week 24 and Week 52  
16. Change from baseline in biomarkers of cardiac stress such as N-terminal prohormone of brain 
natriuretic peptide (NT-proBNP) at Week 24 and Week 52  
17. Change from baseline in RBC indices, such as mean corpuscular volume (MCV) at Week 24 and 
Week 52  
18. Change from baseline in each measured subdomain of ASCQ-Me questionnaire at Week 24 and 
Week 52  
19. Change from baseline in total preference score and individual domain scores of PROPr 
questionnaire at Week 24 and Week 52 
20. Change from baseline in overall score of the Sickle Cell Self-Efficacy Scale (SCSES) at Week 24 
and Week 52 


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Some of the other secondary endpoints listed above include multiple endpoints at multiple time points. In 
terms of the hierarchical order of the testing, the endpoint listed earlier will be tested first for the earlier time 
points, before the endpoint listed later. For example, for point #9, it will be considered as 4 endpoints in the 
order of: 
- 
Change from baseline in HbF (%) at Week 24 
- 
Change from baseline in F-cells (%) at Week 24 
- 
Change from baseline in HbF (%) at Week 52 
- 
Change from baseline in F-cells (%) at Week 52 
For points #18 and #19, the individual domains are in the order as listed in Section 13.5.4. 
12.5 Data Monitoring Committee 
The specific activities of the DMC will be governed by a charter which will define the DMC’s membership, 
meeting frequency, procedures/conduct, and requirements for reporting its observations to the sponsor. 
To ensure safety oversight throughout the trial, the DMC will review safety and preliminary efficacy data 
and provide recommendations to the Sponsor as described below. 
The DMC will convene at the following times and for the following activities during the trial: 
• 
Review safety data for at least 5 subjects who received IMR-687 at the lower dose and make 
recommendation as to the inclusion of the higher dose. This potential study adjustment makes                  
the design adaptive. 
• 
Review safety data to confirm acceptable safety and tolerability of the higher dose of IMR-687 
and make recommendation as to whether the dose levels could be modified. 
• 
Review safety data on a periodic basis. 
• 
At any time during the trial—upon request by the Sponsor, medical monitor, or DMC—should a 
concern arise from emerging safety data for which DMC review and assessment is desired. This 
includes the emergence of a frequency or pattern of AEs or SAEs that suggests an unexpected or 
otherwise concerning safety signal. At any time, the DMC may recommend stopping a dose arm 
or the study for safety concerns. 
The DMC may review the following subject data, depending on the scope of the meeting, and may 
recommend that the study continues as planned, that the protocol be modified, that a dose level should be 
stopped (which will inform the highest tolerated dose for analyses), or that the study terminate for safety 
concerns: 
• 
Unblinded safety, PK, and preliminary efficacy/PD data, which may include TEAEs, SAEs, PK 
data, clinical laboratory test results, vital signs, and other relevant data for all subjects 
randomized. 
• 
The DMC chairperson will receive copies of all SAE reports for ongoing review during the study. 
The DMC chairperson may forward an SAE report to the full DMC if he/she feels that their 
immediate input on, or awareness of, the SAE would be helpful. 
• 
Additional unblinded summary reports (at group level) for IA and FA. 
All assessments, decisions, and recommendations by the DMC will be documented in writing as noted in 
the DMC charter and prior to any resultant changes to the study unless their immediate implementation is 
considered necessary for subject safety.  


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 Statistical Methods 
All statistical analyses will be conducted using SAS Version 9.4 or other validated software. 
Descriptive summary statistics will be provided for demographics, disposition, and treatment exposure. 
The number and percentage of subjects who discontinue from the study, along with reasons for 
discontinuation will be tabulated. 
Continuous data will be summarized using descriptive statistics (number of subjects, mean, SD, median, 
first quartile (Q1), third quartile (Q3), minimum, and maximum, as well as geometric statistics as 
applicable). Counts and percentages will be used for summarizing categorical (discrete) data. For 
summaries of categorical variables, counts and percentages are based on the number of subjects in the 
analysis set unless otherwise specified. 
All statistical tests and resulting p-values will be reported as 2-sided. Two-sided confidence intervals, 
when presented, will generally be constructed at the 95% level. P-values should be presented to 4 
decimal places, with values less than 0.0001 presented as <0.0001. Multiplicity adjustment will be used 
for the IA and FA using the Lan-DeMets alpha spending function, as specified in Sections 12.3 and 
Section 12.4. 
In general, means and medians will be presented to 1 or more decimal places than the recorded data. 
The SDs will be presented to 2 more decimal places than the recorded data. Confidence intervals about a 
parameter estimate will be presented using the same number of decimal places as the parameter 
estimate. Percentages will be presented to 1 decimal place.  
A month is operationally defined to be 30.4375 days. A year is operationally defined to be 365.25 days. 
If a subject was assigned the wrong stratum at randomization, their stratum based on the randomization 
system will be used for the statistical analyses. Analyses may be repeated using actual stratum if mis-
randomization occurs in more than 10% of randomized subjects.  
Where specified, there will be pair-wise comparisons between IMR-687 higher dose vs placebo, IMR-687 
pooled dose vs. placebo, and IMR-687 lower dose vs placebo. Of note, by study design, subjects will be 
randomly assigned in a 2:1 ratio to receive either IMR-687 lower dose or placebo respectively at phase 
one of the trial. When the DMC recommends inclusion of the higher dose, randomization will then 
proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose, or placebo), as the second phase. 
The placebo and lower dose from the two phases will be analyzed together without any adjustment in the 
statistical analysis.   
The following labels will be displayed in tabulations, unless otherwise specified: 
Table 6 Treatment Groups in Tabulations 
Placebo  
IMR-687  
200/300 mg 
IMR-687  
300/400 mg 
IMR-687 Pooled 
Dose 
Total 
 
The total column will only be included in the concomitant medication summaries and in the summaries 
pertaining to information collected before the treatment started, such as demographic, baseline and 
disease characteristics and prior medications.  
In general, all clinical data collected from CRF, or laboratory will be stored in SDTM datasets in STDM 
structure and presented in subject listings.  
13.1 Subject Disposition 
The number of subjects screened, randomized, and treated in the study will be presented, together with 
the number and percentage of subjects who discontinued study drug along with the primary reason for 
study drug discontinuation, discontinued from the study and the primary reason for study discontinuation.  
A tabulation of the number and percentage of subjects included in each analysis set will be provided.  


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Details regarding randomization assignments, subjects who discontinued study drug and/or study, and 
subject analysis sets will be reported in by-patient listings. 
A separate listing will be provided for the replacement subjects and the subjects replaced, including their 
demographic and stratification factors. 
13.2 Important Protocol Deviations 
Prior to the database lock for the primary analysis, the Sponsor or designee medical and statistics 
personnel will identify and review any deviations from the study protocol. Any protocol deviations that 
might significantly affect the completeness, accuracy, and/or reliability of the study data or that might 
significantly affect a subject's rights, safety, or well-being will be classified as important protocol 
deviations (FDA, ICH, 2013, January).  
Tabulation of the number and percentage of subjects with important protocol deviations by center and 
category within each treatment arm will be presented on the Safety Analysis Set. Categories will be 
sorted alphabetically, and deviations within each category will be sorted alphabetically. Categories will 
include: 
• 
Deviations related to study inclusion or exclusion criteria 
• 
Receipt of any prohibited therapies as defined in the protocol 
• 
Significant deviations in study drug administration 
• 
Subjects were not withdrawn after developing withdrawal criteria during the study. 
Details for protocol deviations for subjects in the Safety Analysis Set will be provided in the protocol 
deviations data listing. 
13.3 Exposure and Drug Accountability 
A summary of exposure and compliance, to be reported on the safety analysis set, will include the total 
number of tablets taken, compliance (%), total exposure (mg), average daily dose (mg/day), duration of 
exposure (in weeks), and incidence and duration of dose interruption. These parameters will be 
calculated as follows: 
• 
Duration of exposure (in weeks) will be calculated as [(date of last dose of study medication – 
date of first dose of study medication + 1)/7]. The date of first dose of study medication will be 
collected from the Study Drug Administration CRF page and the date of last dose of study 
medication will be collected from the End of Treatment CRF page. If there is no date for end of 
treatment on the End of Treatment CRF page, the last available dose date will be used. See 
Appendix 4 for a complete set of data handling rules. 
• 
Total number of tablets taken = total number of tablets dispensed – total number of tablets 
returned. The total number of tablets dispensed and returned will be collected from study drug 
accountability CRF Page. They are to be collected at study visits and will be summed over the 
whole study treatment period. 
• 
Total exposure (mg) of IMR-687 = Total number of tablets taken * tablet dose level (100/150/200 
mg). IMR-687 will be supplied as 100, 150, or 200 mg white tablets in the study. In the lower dose 
group (≥3.0 to ≤4.5 mg/kg), subjects weighing <67 kg will be dispensed 100 mg tablets and those 
weighing ≥67 kg will be dispensed 150 mg tablets. In the higher dose group (4.5 to ≤6.7 mg/kg), 
subjects weighing <67 kg will be dispensed 150 mg tablets and those weighing ≥67 kg will be 
dispensed 200 mg tablets. The dose regimen for all subjects is 2 tablets once daily.  The weight 


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at the baseline will be used to establish the dose level and the same dose level will be used 
throughout the trial. 
• 
Incidence and duration of dose interruption: as collected from the IP Interruptions CRF page. 
• 
Overall compliance (%) = [(total number of tablets dispensed – total number of tablets returned) / 
duration of exposure (days)] x 100.  
• 
Average daily dose (mg/day) = total exposure (mg) / duration of therapy (days). 
Additional considerations and data handling in exposure and drug accountabilities will be needed for the 
DMC and IA when some of drug dosing and accountability information is deemed incomplete. See 
Appendix 4 for a complete set of data handling rules for drug exposure and accountability. 
The same tabulation will be generated for the ITT, mITT and PP analysis set if it is not the same as the 
safety analysis set. 
Details of the administration of study drug, including randomized and actual treatment, start date and time 
of each dose, dose per administration, and date, time, and composition of last meal will be listed on the 
safety analysis set. 
Details of study drug accountability including date dispensed, date returned, amount returned, and 
compliance per dosing period (in %, as collected directly from CRF), overall compliance (in %, for the 
whole duration of study drug exposure, as calculated as above) will be listed based on the safety analysis 
set. 
13.4 Demographic and Baseline Characteristics 
Demographics, baseline and disease characteristics will be summarized for all analysis sets. The 
following are included: 
• 
Age (years) –as a continuous variable  
• 
Sex (Female, Male) 
• 
Ethnicity (Categories as collected from CRF) 
• 
Race (Categories as collected from CRF) 
• 
Region (North America/Europe, Africa/Middle East) 
• 
Height (cm) 
• 
Weight (kg) 
• 
BMI (kg/m2) 
• 
Diagnosis Type (HbSS, HbSB0 thalassemia, HbSB+ thalassemia) 
• 
Baseline HU Use (as collected from IRT) 
• 
Actual Baseline HU Use (as collected from Prior and Concomitant Medications CRF) 
• 
Number of VOCs in the past 12 months (in categories of 1, 2-4, 5-7, 8-12 and as a continuous 
variable)  
• 
The number of hospitalizations for VOCs in the past 12 months ((in categories of 1, 2, 3, ≥ 4 and 
as a continuous variable) 
• 
Baseline HbF - as a continuous variable  


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• 
Baseline Hb - as a continuous variable  
The median value of Age and Baseline HbF/Hb will be determined by the median in the ITT analysis set 
and displayed as a numeric value in tabulations.  
13.4.1 Medical and Surgical history 
Medical and Surgical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
version 23.0 or higher) and will be summarized for the safety analysis set, by treatment group and overall, 
using System Organ Class (SOC) and MedDRA preferred term (PT). The table will include the number 
and percentage of subjects and will be sorted alphabetically by SOC and in decreasing frequency by PT 
and then alphabetically for ties (based on the total count in the analysis set). A subject will only be 
counted once within a class.  
A by-patient listing will show medical and surgical history generated on the safety analysis set. 
13.4.2 Prior and Concomitant Medications 
Concomitant medications are medications ongoing at the time of the first dose of study drug or 
medications that started after first dose and within 30 days of the last dose of study drug. Any medication 
that was used at any time prior to the date of first study drug is a Prior Medication. 
Medications will be captured on the Prior and Concomitant Medications CRF and coded using the WHO 
Drug dictionary (WHODDE 01MAR2020 or later version). 
Prior medication and concomitant medications will be summarized separately by Anatomical Therapeutic 
Chemical (ATC) Level 2 and preferred terms for the safety analysis set. If ATC-2 is missing, the next non-
missing level will be used. The summary will be sorted by ATC class alphabetically, then by descending 
frequency for preferred term in the pooled IMR-687 dose column and then alphabetically for ties. A 
patient will only be counted once within each ATC class and within each preferred name. 
Medications related to sickle cell disease can be identified in the Prior and Concomitant Medications CRF 
when the Primary Reason Medication = Disease Under Study. Prior medication and concomitant 
medications related to sickle cell disease will be summarized separately, in a similar manner as for the 
general prior and concomitant medications. 
In addition, opioids and pain medications will be identified via Standardized Drug Groupings (SDGs) and 
the concomitant use of opioids and the concomitant use of pain medications will be summarized in a 
similar manner as for concomitant medications. 
All prior and concomitant medications data will be presented in a listing for the safety analysis set. 
13.4.3 Concomitant Procedures 
The number and percentage of subjects having concomitant procedures will be tabulated for the safety 
analysis set by treatment group using MedDRA (version 23.0 or later). Procedures will be classified by 
SOC, then by PT. Subjects will only be counted once within each SOC and PT.  The SOCs and PTs will 
be sorted in descending frequency, using the numbers in the higher dose IMR-687 treatment arm, and 
then alphabetically in the event of any ties. 
All concomitant procedures data will be presented in a listing based on the Safety Analysis Set. 
13.5 Endpoint Analyses 
13.5.1 Summary of Analyses 
Primary efficacy endpoint, safety endpoints, secondary efficacy endpoints, and corresponding analysis 
methods are summarized in Table 7 below. Exploratory analyses are detailed in Section 13.5.5. 


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Table 7 Summary of Efficacy and Safety Analyses   
Endpoints 
Analysis 
Time 
Points 
Analysis Methods  
Analysis 
Set 
Time 
Point for 
analysis 
Primary Efficacy 
• 
Annualized rate of 
VOCs 
NA 
Comparison of median differences 
among treatment groups using Stratified 
Wilcoxon rank-sum tests, with 
stratification factors of region and HU 
use. The van Elteren test may be used 
for the evaluation of treatment difference 
across strata. P-values for each active 
group (including pooled IMR-687) vs. 
placebo  
ITT as 
primary 
analysis set, 
mITT, PP as 
sensitivity 
 
IA, FA 
Safety 
NA 
Descriptive statistics 
Safety 
IA, FA 
Secondary Efficacy 
• 
Time to first VOC 
• 
Time to second VOC 
NA 
Stratified log rank test, and stratified Cox 
regression model. p-values from a 
stratified log rank test and hazard ratios 
(with 95% CIs) estimated from a 
stratified Cox regression model with 
treatment arm and stratification factors 
of region and HU use as covariates will 
be provided for comparison of each 
active group (including pooled IMR-687) 
vs. placebo 
ITT as 
primary 
analysis set, 
mITT, PP as 
sensitivity 
IA* , FA 
• 
Annualized rate of 
VOC-related 
hospitalizations 
• 
Annualized rate of 
days hospitalized for 
VOC-related 
hospitalizations 
NA 
Stratified Wilcoxon rank-sum tests, with 
stratification factors of region and HU 
use. P-values for each active group 
(including pooled IMR-687) vs. placebo  
ITT as 
primary 
analysis set, 
mITT, PP as 
sensitivity 
IA*, FA 
• 
Proportion of VOC-free 
subjects 
• 
HbF responder rate at 
Week 24 and Week 52 
• 
Hb responder rate at 
Week 24 and Week 52 
 
NA 
Stratified CMH test adjusted for 
stratification factors of region and HU 
use. 
ITT as 
primary 
analysis set, 
mITT, PP as 
sensitivity 
IA*, FA 
Change from baseline at 
Week 24 and Week 52  
• 
HbF (%)  
• 
F-cells (%)  
• 
Total Hb (g/dL)  
 
 
Baseline 
to Week 
24 and 
Baseline 
to Week 
52 
MMRM analysis with fixed effects for 
treatment, visit, and treatment-by-visit 
interaction, and baseline value, region, 
and HU use as covariates. Mean (95% 
CI), Mean difference (95% CI), and p-
value will be provided (IA/FA). Both 
change from baseline and percentage 
change from baseline will be analyzed 
(IA/ FA). 
ITT as 
primary 
analysis set, 
mITT, PP as 
sensitivity 
FA   
 
  
Change from baseline at 
Week 24 and Week 52 
• 
Biomarkers of RBC 
Hemolysis (% and 
Baseline 
to Week 
24, 
MMRM analysis with fixed effects for 
treatment, visit, and treatment-by-visit 
interaction, and baseline value, region, 
and HU use as covariates. Mean (95% 
CI), Mean difference (95% CI), and p-
ITT, mITT 
FA 


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Endpoints 
Analysis 
Time 
Points 
Analysis Methods  
Analysis 
Set 
Time 
Point for 
analysis 
absolute reticulocytes, 
unconjugated [indirect] 
bilirubin and LDH) 
• 
Biomarkers of 
adhesion such as 
Soluble E-sel, P-sel, 
ICAM-1, and VCAM-1 
• 
Biomarkers of 
inflammation such as 
hsCRP and MPO 
• 
Biomarkers of cardiac 
stress such as NT-
proBNP 
• 
RBC indices, such as 
MCV 
Baseline 
to Week 
52 
value will be provided. Both change from 
baseline and percentage change from 
baseline will be analyzed. 
Change from baseline at 
Week 24 and Week 52  
• 
Each measured 
subdomain of Adult 
Sickle Cell Quality of 
Life Measurement 
Information System 
(ASCQ-Me) 
questionnaire  
• 
Total preference score 
and individual domain 
scores of the Patient-
Reported Outcomes 
Measurements 
Information System – 
Preference (PROMIS 
29 + 2 Profile v2.1 
[PROPr]) questionnaire  
• 
Overall scores of the 
Sickle Cell Self-
Efficacy Scale 
(SCSES) 
Baseline 
to Week 
24, 
Baseline 
to Week 
52 
ANCOVA analysis with fixed effects for 
treatment, and baseline value, region, 
and HU use as covariates. Mean (95% 
CI), Mean difference (95% CI), and p-
value will be provided.   
ITT 
FA 
* Key secondary and other secondary endpoints will be tested in hierarchical order through a gatekeeping procedure.  
13.5.2 Primary Efficacy Analysis 
The primary efficacy endpoint, annualized rate of VOCs, will be analyzed using a stratified Wilcoxon rank-
sum test based on stratification factors of region (North America/Europe vs. Africa/Middle East) and HU 
use (Yes vs. No) to compare the treatment effect of IMR-687 to placebo using the ITT population.  
The van Elteren nonparametric test may be used for the evaluation of treatment difference across strata. 
The homogeneity of strata results for HU use and region will be investigated prior to the use of the 
stratified Wilcoxon test. If the data is homogeneous, we will perform the primary analysis stratifying for 
both region and HU use for the primary analysis and then for HU use only as supplementary analysis at 
the final analysis. 


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13.5.2.1 Derivation of Annualized Rate of VOCs 
As described in Protocol Inclusion Criterion 3, a VOC is defined as a documented episode of acute 
painful crisis (for which there was not an explanation other than VOC) that involves moderate to severe 
pain lasting for at least 2 hours and at least one of the following: 
• 
Use of escalated analgesia (including healthcare professional-instructed use of an analgesic 
prescription) 
• 
A hospital, emergency department, or clinic visit and/or healthcare telephone consultation at the 
time of occurrence 
• 
Diagnosis of acute chest syndrome (ACS) (defined as an acute illness characterized by fever 
and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray), 
hepatic sequestration, or splenic sequestration, or priapism (in males)  
VOCs collected during the study are assumed to meet these criteria as well. 
VOC information, including start and end date/time, primary setting for treatment (hospitalization/ 
emergency department, etc.), and treatments are collected on the “VOC” CRF page.  
Annualized rate of VOCs is calculated as Total number of VOCs / ([Date of last dose of study drug– date 
of first dose of study drug + 1]/365.25).   
Date of last dose of study drug is collected from the “End of Treatment” CRF page. If that date is not 
available (which is expected for some of the subjects in the IA), the data cut-off date will be used. 
13.5.2.2 Primary Analysis of Primary Efficacy Endpoint 
For the primary efficacy analysis, the following hypotheses (H0 and Ha) will be tested first: 
H0: The annualized rate of VOCs between IMR-687 highest tolerated dose and placebo = 0 
Ha: The annualized rate of VOCs between IMR-687 highest tolerated dose and placebo ≠ 0 
If the above testing is successful, the following hypotheses (H1 and Hb) will be tested: 
H1: The annualized rate of VOCs between pooled IMR-687 and placebo = 0 
Hb: The annualized rate of VOCs between IMR-687 pooled and placebo ≠ 0 
If the above testing is successful, the following hypotheses (H2 and Hc) will be tested: 
H2: The annualized rate of VOCs between IMR-687 lower dose and placebo = 0 
Hc: The annualized rate of VOCs between IMR-687 lower dose and placebo ≠ 0 
A stratified Wilcoxon rank-sum test based on stratification factors of region (North America/Europe vs. 
Africa/Middle East) and HU use (Yes vs. No) will be used to compare the treatment effect of IMR-687 to 
placebo in the ITT analysis set and a two-sided p-value will be provided. The homogeneity of strata 
results will be investigated prior to conducting the primary analysis at the end of the study.  
The primary endpoint comparison will be performed at both the IA and FA. The critical values for the 
significance are calculated based on a Lan-DeMets alpha spending function for IA (See Section 12.2 for 
details), and the propagated alpha will be used for FA. If the two-sided p-value from the primary 
comparison is below the critical values for the significance in IA or FA (in favor of IMR-687 highest 
tolerated dose), the study is considered a success in terms of efficacy. If this boundary is crossed during 
the IA, the study may be unblinded and patients receiving placebo may be offered active treatment. See 
Section 12.4 for details on the alpha control and hierarchical testing procedures. 


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13.5.2.3 Missing Value Consideration for the Primary Efficacy Analysis 
The value of the primary endpoint, annualized rate of VOCs, will be non-missing by definition. However, 
subjects included in the ITT analysis may not all complete the 52-week treatment period. In the context of 
this endpoint, the unobserved VOC events after treatment discontinuation will be considered missing 
values. This calculation accounts for early treatment discontinuation by extrapolating the VOC rate 
annualized to one year. The primary analysis assumes the unobserved rate of VOC will be the same for 
the observed rate for the same subject. 
Missing data will not be imputed for primary endpoint analysis methods. Data imputation strategies will be 
employed for sensitivity analysis.   
Understanding the reasons why data are missing is important to correctly interpret and handle the 
observed data. If the missing data mechanism is independent of missing outcome values, conditional on 
earlier observed outcome variables and/or covariates, the outcome values are missing at random (MAR). 
If the probability of missingness depends on an outside variable not in the model or is related to 
unobserved outcome values at the time of dropout and possibly afterward then the values are missing not 
at random (MNAR).  
Table 8 summarizes the classification with the potential reasons. The missing data pattern will be 
summarized and the impact of these missing values will be explored in the sensitivity analysis below. 
Table 8 Classification of Missing Data Pattern 
Missing Data Pattern 
Reason for Treatment Discontinuation 
MNAR (Missing Not at Random) 
Due to efficacy/safety related reasons:  
• 
Adverse Event  
• 
Death 
• 
Lack of Efficacy 
• 
Lost to Follow-up 
• 
Non-Compliance with Study Protocol 
• 
Non-Compliance with Study Drug 
• 
Physician Decision 
• 
Study Terminated by Sponsor 
• 
Subject Participation in Another 
Investigational Study  
• 
Trial Site Terminated by Sponsor 
• 
Withdrawal of Consent 
• 
Other (efficacy/safety related) 
MAR (Missing at Random) 
Due to non-efficacy/non-safety related reasons:  
• 
Pregnancy 
• 
Study Blind Intentionally or Accidentally 
Broken 
• 
Subject Erroneously Included in Study 
(i.e. did not meet eligibility criteria) 
• 
COVID-19 
• 
Other (not efficacy/safety related) 
 
13.5.2.4 Sensitivity Analyses for Primary Efficacy Analysis  
A number of sensitivity analyses will be performed for the primary endpoint, annualized rate of VOCs, to 
examine the robustness of the results: 
1. Sensitivity analysis will be conducted on the mITT and PP analysis sets 


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2. Sensitivity analysis using negative binomial regression (or Poisson regression as appropriate) 
with total number of VOCs as dependent variable, log treatment exposure as an offset, 
stratification factors and treatment as independent variables. The analysis will be performed on 
the ITT, mITT and PP analysis sets. 
3. Tipping Point Analysis #1 - P-Value Frontiers 
The primary analysis method for annualized rate of VOCs is stratified Wilcoxon rank-sum test. 
This sensitivity analysis is to explore the sensitivity of the Wilcoxon rank-sum test on the 
distribution of observed data.  
In this tipping point analysis, the annualized rate of VOCs for the IMR-687 highest tolerated dose 
subjects and placebo subjects will be shifted separately (change by -50% to +50% at individual 
subject level) and the results (median difference, Interquartile range [IQR] and p-value) from 
stratified Wilcoxon rank-sum test for each combination of the shifts will be tabulated. P-Value 
Frontiers will be identified when the p-value has changed from non-significant to significant, or 
vice versa. The tipping point analysis will be performed on the ITT analysis sets. 
4. Sensitivity analysis for Missing values due to early discontinuation 
In the primary analysis of annualized rate of VOCs, there is an underlying assumption that the 
unobserved rate of VOCs after study discontinuation will be the same as the observed rate for the 
same subject. Several sensitivity analyses will be performed to examine this assumption and its 
impact. The analysis below will be performed on the ITT analysis set. 
4.1 Completer, non-completer, and pooled analysis 
The primary analysis will be repeated for subjects who completed the study treatment period 
and who did not separately, and combined subject populations will be analyzed, to explore 
the differences between the annualized rates of VOCs among completers, discontinued 
patients, and the combined patient group.   
For the pooled analysis, a jump-to-reference (J2R) method will be applied to non-completers 
in order to combine them with completers. In the jumped-to-reference method, after dropout, 
the subject's outcomes (events of VOC) are assumed to “jump” to those of the reference 
group (completers in the placebo group).  
For a subject in the IMR-687 dose groups who dropout, the annualized rate of VOCs will be 
recalculated as: 
[Total number of observed VOCs during treatment period + annualized rate from Placebo 
completers * (Date of expected last study drug if not discontinued - Date of last dose of 
study drug + 1)]/365.25 
The annualized rate from Placebo completers will be the median (or average when median is 
0) rate of all Placebo completers. Date of expected last study drug if a subject is not 
discontinued is calculated as First Dose Date + 364 days (52 weeks). Dropout subjects in the 
Placebo group will not require additional imputation. 
4.2 Tipping Point Analysis #2 – MNAR with J2R 
This tipping point analysis will be based on the J2R reference imputation, where the 
reference refers to the average annualized rate of VOCs among the completers in the 
placebo group in Section 4.1 Assuming the p-values for the primary comparison (highest 
tolerated dose vs placebo) are still significant with J2R (using prorogated alpha from IA), 
incremental changes (delta) in the referenced rate will be applied to the periods deemed to 
be MNAR, for the dropout subjects in the IMR-687 dose groups. If during the course of 
incrementing delta, the study conclusions change from favorable to unfavorable for the IMR-
687 highest tolerated dose group, a tipping point is reached. The delta change will start from 
0, and increment at a rate of 0.5 event/year, but granularity can be adjusted by incrementing 
by smaller or large amounts as needed.  


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4.3 Multiple Imputation Under MAR 
For the discontinued subjects, alternative to the J2R method, the annualized rate of VOCs 
after dropout will be imputed using multiple imputation under MAR. MAR assumes the 
missing value is independent of unobserved outcomes given observed data (i.e., annualized 
rate of VOCs after dropout can be modeled based on subjects with observed annualized rate 
of VOCs). 
The following steps will be implemented: 
Step 1: 
A fully conditional specification (FCS) method will be used to impute the missing annualized 
rate of VOCs after dropout using a regression model. The regression will include the 
covariates of treatment, observed number of VOCs, duration in the study, region (North 
America/Europe vs. Africa/Middle East) and HU use (Yes vs. No). Missing data imputation 
will be performed using the SAS PROC MI procedure. Refer to Appendix 6 for the order of 
variables in the model. 
Step 2: 
For each of the repetitions in the datasets, the total number of VOCs for the entire study will 
be recalculated for the dropouts as: 
 
 [Total number of observed VOCs during treatment period + annualized rate of VOCs after 
dropout * (Date of expected last study drug if not discontinued - Date of last dose of study 
drug + 1)]/365.25 
Step 3: 
The negative binomial regression (or Poisson regression as appropriate) with total number of 
VOCs as dependent variable, log treatment exposure as an offset, stratification factors and 
treatment as independent variables will be run for each of the 100 datasets to obtain 100 
estimators of interest. 
Step 4: 
Use SAS PROC MIANALYZE to produce an overall pooled estimate (mean of 100 estimates) 
The multiple imputation sample code is specified in Appendix 6. However, there could be certain 
adjustments due to unexpected data issues after unblinding treatment. All post-unblinding modifications to 
the multiple imputation model or approaches to address missing data will be described in the CSR. 
13.5.2.5 Supplementary Analysis for Primary Efficacy Analyses 
13.5.3 Subgroup analyses will be performed as supplementary analyses and 
detailed in Section 13.5.6.Key Secondary Efficacy Analysis 
13.5.3.1 Time to first VOC 
The time to first VOC event will be analyzed using Kaplan-Meier methods. Time in months to the first 
VOC event can be calculated as ([date of first VOC event – date of first dose + 1] / 30.4375).  
Both start and end date of VOC event will be collected from “VOC” CRF page. The start date of the VOC 
is not expected to be missing and will be used for the analysis. In the rare event the start date is missing, 
then the end date can be used. If both start date and end date are missing, no imputation will be made 
and the event will be excluded from the analysis.  
Subjects who experience no VOC events during the study will be censored at their study end date (or 
date cut-off date if the study end date is not available). Using the ITT set, the number and percentage of 
subjects with events (subjects who experienced at least 1 VOC on-study) and censored (subjects who did 
not experience any VOCs on-study) will be presented. The 25th, 50th (median), and 75th percentiles, along 


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with associated 2-sided 95% CIs based on the Brookmeyer and Crowley method will be presented. The 
p-values from a stratified log rank test and hazard ratios (and 95% CIs) estimated from a stratified Cox 
regression model with treatment arm and stratification factors (region and HU use) as covariates will be 
presented for comparison of each treatment group to placebo. Kaplan-Meier curves will be produced for 
the time to first VOC with separate curves for each treatment group. 
Sensitivity analysis will be performed for Time to first VOC using the mITT and PP analysis sets. Major 
protocol deviations and subjects (or data) excluded from the PP analysis set will be defined by the 
Sponsor in a blinded manner prior to database lock. No imputation will be performed for the PP analysis. 
13.5.3.2 Other sensitivity analyses may be added. All sensitivity analyses will be 
performed at FA.HbF responder rate at Week 24 
13.5.3.2.1 Analysis and Imputation Methods  
HbF responder rate (as defined by the proportion of subjects with an absolute increase of ≥3% from 
baseline) at Week 24 will be assessed using a stratified Cochran-Mantel-Haenszel (CMH) test adjusted 
for stratification factors of region (North America/Europe vs. Africa/Middle East) and HU use (Yes vs. No). 
The ITT set will be used for this analysis.  
The frequency and percentage of responders and non-responders at Week 24 will be presented for each 
treatment group as well as ORs, RRs, 95% Cis, and p-values from the CMH test comparing active groups 
to placebo.  
Bar plots will be provided, and the proportion of subjects with response in HbF in each treatment group, 
Odds ratios, 95% CI, and p values will be displayed for each treatment comparison.   
The following imputation rules will be applied for the key secondary efficacy endpoint (HbF responder at 
Week 24): 
1. Subject will be treated as a non-responder if there is an initiation of HU post randomization 
and prior to Week 24. 
2. If HbF value is missing at Week 24, the HbF value at Week 16 will be used for the analysis. If 
HbF value at Week 16 is also missing, subject will be treated as a non-responder. 
3. Any HbF value within 8 weeks (56 days) of a RBC transfusion will be excluded from all 
analyses. If the subject does not have a valid HbF value at Week 24 and/or Week 16, subject 
will be treated as a non-responder. 
Number of subjects with imputed values for the key secondary efficacy endpoint and the reason for 
imputation (imputed as non-responder because of initiation of HU post randomization, imputed with Week 
16 value because of Week 24 value is missing, imputed from the last post-baseline assessment prior to 
RBC transfusion) will also be summarized. The observed and imputed Week 24 HbF values will both be 
summarized for the by-visit analysis. 
13.5.3.2.2 Sensitivity Analysis  
Several sensitivity analyses will be implemented to explore robustness of missing value imputation 
methods for the analysis of HbF responder rate at Week 24: 
1. For imputation rule #2 in Section 13.5.3.2.1, use HbF value from Week 12 when Week 24 and 
Week 16 are both missing, i.e. If HbF value is missing at Week 24, HbF value at Week 16 will 
be used for the analysis; If HbF value at Week 16 is also missing, HbF value at Week 12 will 
be used for the analysis; subject will be treated as a non-responder if HbF value is missing for 
Weeks 24, 16 and 12. 
2. For imputation rule #2 in Section 13.5.3.2.1, If HbF value is missing at Week 24, HbF value at 
Week 16 will not be used for the analysis; i.e. Subject will be treated as a non-responder if 
HbF value is missing for Week 24. 


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3. The average value of HbF values at Week 24 and Week 16 will be used to determine if a 
subject is a responder/non-responder at Week 24. If one of them is missing, the other will be 
used for the analysis.  If HbF value at Week 24 and Week 16 are both missing, the subject will 
be treated as a non-responder.   
In addition, sensitivity analyses for HbF responder rate at Week 24 will be conducted using the mITT and 
PP analysis sets. Major protocol deviations and subjects (or data) excluded from the PP analysis set will 
be defined by the Sponsor in a blinded manner prior to database lock. No imputation will be performed for 
the PP analysis. 
All sensitivity analyses above will be performed at FA. 
13.5.3.3 Supplementary Analysis  
Subgroup analysis will be performed for the key secondary efficacy endpoints and detailed in 
Section 13.5.6. Other supplementary analysis may be added. 
13.5.4 Other Secondary Endpoints 
Proportion of VOC-free subjects 
VOC-free subjects are defined as these who did not experience a VOC after the first dose of study drug 
through the end of treatment. Proportion of VOC-free subjects will be analyzed using a stratified Cochran-
Mantel-Haenszel (CMH) test adjusted for stratification factors of region (North America/Europe vs. 
Africa/Middle East) and HU use (Yes vs. No) using the ITT analysis set. Sensitivity analysis will be 
performed for proportion of VOC-free subjects using the PP analysis set. 
Annualized rate of VOC-related hospitalizations  
Annualized rate of VOC-related hospitalization is calculated as total number of VOC-related 
hospitalizations / ([Date of last dose of study drug– date of first dose of study drug + 1] /365.25). 
VOC-related hospitalization will be determined from the “Adverse Event” CRF when the AE’s preferred 
term = “sickle cell anaemia with crisis” and “Did the adverse event result in initial or prolonged 
hospitalization for the subject?” = “Yes”. Date of last dose of study drug are collected from “End of 
Treatment” CRF page. If that date is not available (which is expected for some of the subjects in IA), the 
data cut-off date will be used. 
VOC-related hospitalization-free subjects are defined as these who did not experience a VOC-related 
hospitalization after the first dose of study drug through the end of treatment. 
Analyses of annualized rate of VOC-related hospitalizations will be done in the same way as in 
Section 13.5.2 as for the primary endpoint (annualized rate of VOCs). 
Annualized rate of days hospitalized for VOC-related hospitalizations 
Annualized rate of days hospitalized for VOC-related hospitalizations is calculated as (sum of total 
number of days hospitalized for VOC-related hospitalization / ([Date of last dose of study drug – date of 
first dose of study drug + 1] / 365.25). 
Number of days hospitalized for VOC-related hospitalization is calculated as the sum of (Date of 
Discharge – Date of Admission + 1) for all AEs with preferred term = “sickle cell anaemia with crisis” and 
“Did the adverse event result in initial or prolonged hospitalization for the subject?” = “Yes”.  
Date of last dose of study drug are collected from “End of Treatment” CRF page. If that date is not 
available (which is expected for some of the subjects in IA), the data cut-off date will be used. 
Annualized rate of days hospitalized for VOC-related hospitalization will be analyzed in the same way as 
annualized rate of VOC-related hospitalization. 
 
 


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Time to first for VOC-related hospitalization 
The time to first VOC-related hospitalization event will be analyzed using Kaplan-Meier methods. Time in 
months to the first VOC-related hospitalization event can be calculated as ([date of first VOC-related 
hospitalization event – date of first dose + 1] / 30.4375). 
Time to second VOC 
This analysis of time to second VOC event will be analyzed using Kaplan-Meier methods similar to the 
analysis of the time to first VOC. A patient with less than two VOCs before withdrawal or completion of the 
study is considered censored at the time of withdrawal or completion of the study. 
A sensitivity analysis will be performed separately, excluding these subjects without any VOCs. 
HbF responder rate (as defined by proportion of subjects with an absolute increase of ≥3% in HbF 
from baseline) at Week 52 
This analysis of HbF responder at Week 52 will be similar to the HbF responder rate analysis at Week 24 
(Section 13.5.3.2). Similar imputation rules will apply: 
1. Subject will be treated as a non-responder if there is an initiation of HU post randomization 
and prior to Week 52. 
2. HbF value from Week 36 (the last scheduled visit before the target analysis visit) will be used 
when Week 52 value is missing,  
3. Any HbF value within 8 weeks (56 days) of RBC transfusion is excluded from all analyses.  
Change from baseline in HbF (%) and F-cells (%) at Week 24 and Week 52 
Change and percentage change from baseline in HbF (%) and F-cells (%) will be analyzed using mixed 
models for repeated measures (MMRM) with baseline value as a covariate, fixed effects for region (North 
America/Europe vs. Africa/Middle East), HU use (yes vs. no), treatment, visit, and treatment-by-visit 
interaction. Unstructured covariance matrices will be assumed for all models, but auto-regressive 1 (AR1) 
and compound symmetry (CS) may also be assessed (in that order) if the unstructured covariance matrix 
does not converge.  
Values used at the visit and change from baseline for each parameter will be summarized for each post-
baseline timepoint. The LS Mean estimates and 95% CIs will be displayed for all treatment groups. LS 
Mean difference estimates and 95% CIs with p-values for all IMR-687 treatment groups (relative to 
placebo) will be provided.  
Line plots will be provided for LS mean change from baseline +/- standard error (SE) at each post-
baseline visit by treatment group.  
Waterfall plots will be provided for change in HbF (%) from Baseline to Week 24 and from Baseline to 
Week 52 by treatment group, respectively. The plot of individual subjects change from baseline will be 
displayed with a reference line at 3%.  
If the HbF value at Week 24 and Week 52 were imputed from the previous visits in the responder 
analysis, the imputed value will also be used for the MMRM, summary statistics and waterfall plots. The 
observed value and imputed value will both be presented in the data listing.  
Hb responder rate (as defined by proportion of subjects with an absolute increase of ≥ 1.0 g/dL in 
total Hb from baseline) at Week 24 and Week 52 
This analysis of Hb responder rate at Week 24 and Week 52 will be similar to the HbF responder rate 
analysis at Week 24 and 52. The same imputation rules will apply. 
Change from baseline in total Hb (g/dL) at Week 24 and Week 52 
The analysis of total Hb (g/dL) at Week 24 and Week 52 will be similar to Change (and percentage 
change) from baseline in HbF (%) at Week 24 and 52. 


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Change from baseline in biomarkers of RBC hemolysis (% and absolute reticulocytes, 
unconjugated [indirect] bilirubin, and LDH) at Week 24 and Week 52 
The analysis of change (and percentage change) from baseline in biomarkers of RBC hemolysis at Week 
24 and Week 52 will be similar to the analysis of other change from baseline efficacy variables. The 
analysis will be performed for each of the following parameters, at Week 24 and Week 52 separately: 
• 
% Reticulocytes 
• 
Absolute Reticulocytes 
• 
Unconjugated [indirect] Bilirubin 
• 
Lactate dehydrogenase (LDH) 
Line plots will be provided for LS mean change +/- SE. 
Change from baseline in each measured subdomain of the ASCQ-Me questionnaire at Week 24 
and Week 52 
The Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me®) is a systemic, 
reliable, and valid method for documenting adult SCD patient-reported outcomes. The questions are 
grouped into 3 domains (physical, social, and emotional) encompassing 7 subdomains, of which the 
following 5 will be measured: emotional impact, pain impact, sleep impact, social functioning impact, and 
stiffness impact. Of note, pain episodes and frequency, and SCD medical history checklist will not be 
evaluated, but the reliability of the instrument should allow for use of only a subset of the validated 
domains. Each subdomain includes 5 to 9 items. Recall periods vary by subdomain and even question, 
with most of the periods being from 7 days to 30 days. Subdomain scores are standardized to have a 
mean of 50 and a standard deviation of 10.  
Each of the five subdomains measured in this study consists of five questions. Responses to each 
question range in numeric value from 1 (Always/Very/Very much) to 5 (Never/Not at all). To calculate 
each subdomain score, responses to each of the 5 questions will be summed, and then converted to T-
scores with standard errors (SE) based on the scales in Appendix 1. If any question within a subdomain is 
not answered, the subdomain score will be missing for that subject/time point. Untransformed scores 
range from 5 to 25, and the range of converted scores depends on the subdomain. Higher scores indicate 
healthier status.  
The analysis of change from baseline in each measured subdomain of the ASCQ-Me questionnaire at 
Week 24 and Week 52 will be based on an analysis of covariance (ANCOVA) model with fixed effects for 
treatment, visit, and treatment-by-visit interaction, and baseline value, region, and HU use as covariates. 
Mean (95% CI), Mean difference (95% CI), and p-value will be provided. The T-score analysis will be 
performed for each of the following parameters (subdomains), at Week 24 and Week 52 separately: 
• 
Emotional Impact 
• 
Pain Impact 
• 
Sleep Impact  
• 
Social Functioning Impact  
• 
Stiffness Impact  
Line plots will be provided for LS mean change +/- SE. 
Change from baseline in total preference score and individual domain scores of the PROPr 
questionnaire at Week 24 and Week 52 
The PROMIS-29+2 Profile (PROPr) questionnaire (version 2.1) consists of seven domain scores 
(Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, Ability to Participate in Social Roles 


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and Activities, and Pain Interference), as well as a Cognitive Function short form and a Pain Intensity 
question. Each domain consists of four questions. Responses to each question range in numeric value 
from 1 (Unable to do/Never/Not at all/Very poor) to 5 (Without any difficulty/Always/Very much/Very 
good). The Cognitive Function short form consists of two questions where responses range from 1 (Not at 
all) to 5 (Very much). To calculate each domain score and cognitive function score, responses to each of 
the 4 questions (or 2 questions for the cognitive function) will be summed, and then converted to T-scores 
with SE based on the scales in Appendix 2. If any question within a domain is not answered the domain 
score will be missing for that subject/time point. Untransformed scores range from 4 to 20, and the range 
of converted T-score depends on the domain. Higher scores indicate a healthier status. 
The total preference (PROPs) score will be calculated using SAS codes provided in Appendix 1 of “The 
Development of a Preference-based Scoring System for PROMIS (PROPr): A Technical Report (v1.4)” by 
Hanmer and Dewitt (December 2017). The PROPs score is between 0 and 1 with higher scores indicating 
better quality of life. 
The analysis of change from baseline in total preference score and individual domain T-scores of the 
PROPr questionnaire at Week 24 and Week 52 will be similar to the analysis of ASCQ-Me. The analysis 
will be performed for each of the following parameters, at Week 24 and Week 52 separately: 
• 
Total Preference Score  
• 
Physical Function 
• 
Anxiety 
• 
Depression 
• 
Fatigue  
• 
Sleep Disturbance 
• 
Ability to Participate in Social Roles and Activities  
• 
Pain Interference 
• 
Cognitive Function 
• 
Pain Intensity 
Line plots will be provided for LS mean change +/- SE. 
Change from baseline in overall score of the SCSES at Week 24 and Week 52 
The Sickle Cell Self-Efficacy Scale (SCSES) is a 9-item QoL measure for adults with SCD. This measure 
is a self-appraisal of an SCD patient’s ability to engage in daily functional activities and to manage SCD 
symptomatology. Response choices range from “not at all sure” to “very sure”. Responses from individual 
items are summed to give an overall score with higher scores indicating greater self-efficacy for coping 
with SCD. If the response for any of the individual questions is missing, the overall score will be missing. 
The analysis of change from baseline in overall score of the SCSES at Week 24 and Week 52 will be 
similar to the analysis of ASCQ-Me. The analysis will be performed for Week 24 and Week 52 separately. 
Line plots will be provided for LS mean change +/- SE. 
Change from baseline in biomarkers of adhesion at Week 24 and Week 52 
The analysis of change (and percentage change) from baseline in biomarkers of adhesion at Week 24 
and Week 52 will be similar to the analysis of other change from baseline efficacy variables. The analysis 
will be repeated for each of the following parameters, at Week 24 and Week 52 separately: 
• 
Soluble E-sel  


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• 
P-sel  
• 
ICAM-1 
• 
VCAM-1  
Line plots will be provided for LS mean change +/- SE. 
Change from baseline in biomarkers of inflammation at Week 24 and Week 52 
The analysis of change (and percentage change) from baseline in biomarkers of inflammation at Week 24 
and Week 52 will be similar to the analysis of other change from baseline efficacy variables. The analysis 
will be performed for each of the following parameters, at Week 24 and Week 52 separately: 
• 
hsCRP  
• 
MPO  
Line plots will be provided for LS mean change +/- SE. 
Change from baseline in biomarkers of cardiac stress at Week 24 and Week 52 
The analysis of change (and percentage change) from baseline in biomarkers of cardiac stress at Week 
24 and Week 52 will be similar to the analysis of other change from baseline efficacy variables. The 
following parameter will be analyzed at Week 24 and Week 52 separately: 
• 
NT-proBNP  
Line plots will be provided for LS mean change +/- SE. 
Change from baseline in RBC indices at Week 24 and Week 52 
The analysis of change (and percentage change) from baseline in RBC indices at Week 24 and Week 52 
will be similar to the analysis of other change from baseline efficacy variables. The following parameter 
will be analyzed at Week 24 and Week 52 separately: 
• 
MCV  
Line plots will be provided for LS mean change +/- SE. 
13.5.5 Exploratory Efficacy Endpoints 
The analysis of change (and percentage change) from baseline in renal function at Week 24 and Week 
52 will be similar to the analysis of other change from baseline efficacy variables. Change from baseline 
will be calculated for each of the following renal function parameters at Week 24 and Week 52 separately: 
• 
Urine protein-to-creatinine (Pr:Cr) ratio 
o 
Urine Microalbumin 
o 
Urine ACR (albumin to creatinine ratio) 
• 
Urine Cystatin C 
Line plots will be provided for LS mean change +/- SE. 
Additional exploratory analysis (which are not specified in protocol) will be performed if the data allow, as 
shown in, but not limited to, the list below. In general, the exploratory endpoints will be analyzed following 
the same analysis approach specified for similar endpoints specified in primary and secondary analysis 
sections at FA, unless otherwise specified. 
VOC Analyses:  
• 
Number and percentage of subjects with at least 1 VOC event 


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• 
Number and percentage of subjects by category of number of VOC events: 0, 1, 2-4, 5-7, 8-12, 
13+ 
• 
Number of and percentage of subjects with at least one VOC event lasting for ≥ 48 hours 
• 
Number and percentage of subjects with complicated VOCs (ACS, priapism, hepatic or splenic 
sequestration) 
o 
Number and percentage of subjects with at least 1 ACS 
o 
Number and percentage of males with priapism 
o 
Number and percentage of subjects with hepatic or splenic sequestration 
• 
Number of and percentage of subjects with uncomplicated VOCs 
• 
Time to first event of complicated VOCs 
• 
Annualized rate of days of VOCs (days) 
• 
Annualized VOC rate, excluding subjects with a short period of exposure (< 4 weeks) 
• 
Annualized rate of uncomplicated VOCs  
VOC-Related Hospitalizations: 
• 
Number and percentage of subjects with at least 1 VOC-related hospitalization 
• 
Number and percentage of subjects by category of number of VOC-related hospitalizations: 0, 1, 
2-4, 5-7, >7. 
RBC Transfusions: 
• 
Time to first RBC transfusion  
• 
Number and percentage of subjects with at least 1 RBC Transfusion 
Relationships between biomarkers  
• 
Pairwise correlation (Pearson correlation coefficients and p-values) of annualized rate of VOCs 
and PD parameters (e.g., HbF, Total Hb, F-cells) will be tabulated for Week 24 and Week 52, and 
for HU and non-HU use separately and together. Corresponding scatter plots will also be 
provided. 
13.5.6 Subgroup Analyses  
The following subgroups will be assessed based on the primary, key secondary and PD endpoints (HbF, 
Hb and F-cells). All subgroup analyses will be performed for each subgroup level.  Summary tables and a 
forest plot will display descriptive statistics for each level of a subgroup for a population. 
• 
Age (≤ median and > median of the total population) 
• 
Sex (Female vs Male) 
• 
Region (North America/Europe vs Africa/Middle East) 
• 
Baseline HU use (Yes vs No) 
• 
Baseline number of VOCs (1, 2-4, 5-12) 
• 
Baseline number of VOCs (1, 2-12) [VOC analysis only] 


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• 
Baseline HbF (≤ median and > median of the total population) 
• 
Baseline Hb (≤ median and > median of the total population) 
Baseline HU use are based on the randomization stratum used in IRT. The actual baseline HU use from 
Prior and Concomitant Medications CRF page may be used to perform additional subgroup analysis, if 
they are not same. 
Summary tables and forest plots will be produced to show the treatment difference in the overall 
population and also within each subgroup. The statistics shown will depend on the type of analysis:  
1. Relative risk for the annualized rate of VOCs 
2. Log-rank and Cox Proportional hazards from the time to event  
3. Percentage of responders from responder analysis (HbF and Hb) 
4. LS Mean from MMRM analysis (HbF, Hb, F-cells) 
Statistical models will be used to test if the difference between treatments differs between each level of a 
subgroup (i.e., to test the treatment-by-subgroup interaction).  
It should be noted that the study was not designed to detect treatment differences with high statistical 
power within subgroups. If any subgroup level includes < 5% of all subjects, no inferential statistics will be 
generated. 
13.5.7 Multiplicity Adjustment 
A fixed-sequence statistical strategy tests endpoints in a predefined order, all at the same significance 
level alpha (e.g., α = 0.05), moving to a second endpoint only after a success on the previous endpoint. 
Such a test procedure does not inflate the Type I error rate as long as there is (1) prospective 
specification of the testing sequence and (2) no further testing once the sequence breaks, that is, further 
testing stops as soon as there is a failure of an endpoint in the sequence to show significance at level 
alpha (e.g., α = 0.05). 
Fixed-sequence statistical strategy for multiplicity adjustment will be used in this study.  Endpoints will be 
tested using α = 0.05. The fixed sequence for endpoint testing will follow the order prescribed in section 
12.4.  
13.5.8 Safety Analyses 
In general, safety analyses will be based on the safety analysis set and will be provided by treatment 
group as defined in Section 11.1. The “Total” column will not be included in the summary tabulations.  
Visit windowing (as specified in Section 10.5) will be used to determine the analysis visit for laboratory, 
vital sign and ECG by-visit analyses.  
13.5.8.1 Adverse Events 
MedDRA Coding 
AEs will be coded using MedDRA (v23.0 or higher).  
Treatment-emergent adverse event (TEAE) 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges on or after initiation of 
study drug, or an AE that existed pre-treatment and worsened in severity on or after initiation of study 
drug, through 30 days after the last dose of study drug. A pre-treatment adverse event is an AE emerges 
before the initiation of study drug. 
Refer to Appendix 4 for handling of partial dates for AEs for the purpose of identifying treatment-emergent 
AEs. In the case where it is not possible to define an AE as treatment-emergent or not, the AE will be 
classified as treatment-emergent. 
Severity  


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Severity is classified as Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life-Threatening, 
Grade 5: Death Related to AE, using the Common Terminology Criteria for Adverse Events, v5.0 (CTCAE 
v5.0). For the AE summary by CTCAE severity grade, an AE with missing CTCAE severity grade will not 
be imputed. 
Relationship to Study Treatment  
Relationship is classified as “Unlikely/Not related”, “Possible”, “Probably/Likely”, or “Certain/Related” by 
the Investigator. A “treatment-related TEAE” for the purpose of this summary is defined as a TEAE with 
relationship to study drug of “Possible”, “Probably/Likely” or “Certain/Related”. For the AE summary by 
relationship, an AE with a missing relationship to study drug will not be imputed. Imputed values will not 
be included in data listings. 
TEAEs Leading to Discontinuation of Study Treatment  
TEAEs leading to discontinuation of study treatment will be identified by action taken with study treatment 
being recorded as “Drug withdrawn” on the Adverse events CRF. 
Serious and Non-Serious TEAEs  
Serious adverse events (SAEs) are those events recorded as “Yes” for the question “Was the adverse 
event serious?” on the Adverse Event CRF. 
TEAEs Leading to Death 
TEAEs leading to death are those events which are recorded as “Yes” for the question “Did the adverse 
event result in death?”, or recorded CTCAE Toxicity Grade 5, or with outcome = “Fatal” on the Adverse 
Events CRF. 
TEAEs Leading to Study Discontinuation 
TEAEs leading to study discontinuation are those events which are recorded as “Yes” for the question 
“Did the adverse event cause the subject to be discontinued from the study?” on the Adverse events 
CRF. 
TEAEs Leading to Dose Reduction 
TEAEs leading to dose reduction will be identified by action taken with study treatment being recorded as 
“Dose Reduced” on the Adverse events CRF. 
Overall Summary 
An overall summary of TEAEs will be presented by treatment group for the safety analysis set. The 
number and percentage of subjects reporting any of the following categories will be provided: 
• 
Any pre-treatment adverse event 
• 
Any TEAE 
• 
Grade 3 or higher TEAEs 
• 
Treatment-related TEAEs 
• 
Treatment-related grade 3 or higher TEAEs 
• 
Treatment-related grade 2 or higher TEAEs 
• 
SAEs 
• 
Treatment-related SAEs 
• 
Treatment-related grade 3 or higher SAEs 
• 
TEAEs leading to death 


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• 
TEAEs leading to discontinuation of study drug 
• 
Treatment-related TEAEs leading to discontinuation of study drug 
• 
TEAEs leading to study discontinuation 
• 
Treatment-related TEAEs leading to study discontinuation 
• 
TEAEs leading to dose reduction 
• 
Treatment-related TEAEs leading to dose reduction 
The following AE summaries will be by treatment group, SOC and PT for the safety analysis set. SOCs 
will be sorted alphabetically and PTs will be sorted by descending frequency in the pooled IMR-687 
treatment group column, and then alphabetically for ties. 
• 
The number and percentage of subjects with any TEAE. The AE count will be for subjects not 
events, and subjects are only counted once within each SOC or PT 
• 
The number and percentage of subjects with Grade 3 or higher TEAEs  
• 
The number and percentage of subjects with Treatment-related TEAEs. Subjects with multiple 
events within a particular SOC or PT will be counted under the category of their most drug-related 
event within that SOC or PT (related or not related). AEs will be considered related to study drug 
if they are reported as certain/related, probably/likely related, or possibly related. 
• 
The number and percentage of subjects with Treatment-related TEAEs 
• 
The number and percentage of subjects with Treatment-related Grade 3 or higher TEAEs  
• 
The number and percentage of subjects with Treatment-related Grade 2 or higher TEAEs  
• 
The number and percentage of subjects with SAEs  
• 
The number and percentage of subjects with Treatment-related SAEs  
• 
The number and percentage of subjects with Treatment-related Grade 3 or higher SAEs  
• 
The number and percentage of subjects with TEAEs leading to death  
• 
The number and percentage of subjects with TEAEs leading to discontinuation of study drug 
• 
The number and percentage of subjects with Treatment-related TEAEs leading to discontinuation 
of study drug 
• 
The number and percentage of subjects with TEAEs leading to study discontinuation 
• 
The number and percentage of subjects with Treatment-related TEAEs leading to study 
discontinuation 
• 
The number and percentage of subjects with TEAEs leading to dose reduction 
• 
The number and percentage of subjects with Treatment-related TEAEs leading to dose reduction 
• 
The number and percentage of subjects with TEAEs by severity. Subjects with multiple events 
within a particular SOC or PT will be counted under the category of their most severe event within 
that SOC or PT. AE severity (intensity) will be graded using NCI CTCAE, version 5.0. 


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• 
The number and percentage of subjects with TEAEs by relationship.  Subjects with multiple 
events within a particular SOC or PT will be counted under the category of their most related 
event within that SOC or PT. 
The following AE tables will be summarized by treatment group (without a “Total” column) and PT for the 
safety analysis set. PTs will be sorted by descending frequency, by pooled IMR-687 treatment group 
column, and then alphabetically for ties. 
• 
The number and percentage of subjects reporting each TEAE. 
• 
The number and percentage of subjects reporting common (≥10%) TEAEs (i.e., those occurring 
in at least 10% of subjects in any IMR-687 treatment group) 
• 
The number and percentage of subjects reporting treatment-related TEAEs 
• 
The number and percentage of subjects reporting treatment-related common (≥10%) TEAEs 
All AEs (including non-treatment-emergent events) recorded on the CRF, all SAEs, and all deaths that 
occur following the first dose of study drug will be listed. All AE tables and listings will be reported using 
the safety analysis set. 
13.5.8.2 Laboratory Data 
Clinical laboratory tests (serum chemistry, hematology, urinalysis, and specialty hematology) will be 
summarized using the safety analysis set. Results will be evaluated and presented using the International 
System of Units (SI units) unless otherwise stated. Clinical laboratory values will be graded from Grade 1 
to Grade 4 using NCI CTCAE, version 5.0. Post-baseline laboratory values will only be compared to 
baseline values from the same source. For example, if the baseline value for a parameter came from a 
local laboratory, post-baseline results from the same local laboratory should be used for the analysis. 
Hematology assessments include: RBC count (mean corpuscular volume [MCV], mean corpuscular Hb, 
and mean corpuscular Hb concentration), hematocrit, Hb, platelets, WBC count (with differential: 
basophils, eosinophils, neutrophils, monocytes, and lymphocytes), erythrocyte count, and reticulocyte 
count and reticulocyte percentage. Some of these assessments are also considered PD endpoints, and 
further detailed in the secondary and exploratory endpoint sections above. 
Specialty hematology assessments include: HbF and percent F-cells. 
Coagulation assessments include: PT, aPTT, and international normalized ratio (INR).  
Serum chemistry assessments include: alanine aminotransferase (ALT), albumin, alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), chloride, calcium, 
creatinine, glucose, lactate dehydrogenase (LDH), sodium, potassium, magnesium, phosphate, bilirubin 
(total, direct, and indirect), creatine kinase, total protein, glomerular filtration rate (GFR), and gamma-
glutamyl transferase (GGT). Follicle stimulating hormone (FSH) will be included as well, but this is only 
collected for post-menopausal women at screening. Some of these assessments are also considered PD 
endpoints, and further detailed in the secondary and exploratory endpoint sections above.  
Urinalysis assessments include: appearance, color, pH, specific gravity, ketones, protein, glucose, 
bilirubin, and urobilinogen, including occult blood and microscopic examination of sediment (only if occult 
blood is detected). 
The laboratory results and change from baseline will be summarized by visit by treatment group for 
central laboratory continuous hematology, serum chemistry and urinalysis parameters separately. Note 
that character urinalysis tests will only be listed. 
Shift tables representing the shift from the baseline grade to maximum NCI-CTCAE Grades (Grade I to IV 
and Missing) will be provided for selected hematology and chemistry parameters by visit by treatment 
group. See Appendix 5 for details. 


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Potentially clinically significant (PCS) Criteria for hepatic function and renal function are shown in Table 9 
below. The number and percentage of subjects meeting these PCS criteria will be summarized for hepatic 
function parameters (ALT, AST, ALP, and total bilirubin) and the renal function parameter (serum 
creatinine) separately. Any subject with any post-baseline result (including “unscheduled” visits) meeting 
the criteria will be included in the tabulation. 
Table 9 PCS Criteria for Hepatic Function and Renal Function 
Hepatic Function 
Renal Function 
o Post-baseline Alanine Aminotransferase (ALT) ≥ 3 x upper 
limit of normal (ULN) 
o Post-baseline Aspartate Aminotransferase (AST) ≥ 3 x ULN 
o Post-baseline Direct Bilirubin (BILDIR) ≥ 2 x ULN 
o Post-baseline ALT/AST and BILDIR (ALT≥ 3 x ULN or AST≥ 
3x ULN) and BILDIR≥ 2 x ULN (Hy’s Law) 
 
o Post-baseline Creatinine Clearance 
(CREATCLR) < 0.5 x baseline 
o Post-baseline Serum Creatinine 
(CREAT) > 2 x baseline 
 
 
Creatinine clearance are not directly collected and will be calculated using the Crockroft Gault formula: 
 
All laboratory parameters (serum chemistry, central laboratory hematology, local laboratory hematology, 
specialty hematology, coagulation, and urinalysis) will be displayed in individual subject data listings. 
13.5.8.3 Vital Signs 
Descriptive statistics (N, mean, SD, median, Q1, Q3, minimum, and maximum) will be used to summarize 
vital sign parameters (body temperature, systolic blood pressure, diastolic blood pressure, heart rate, and 
respiratory rate) at baseline, each post-baseline visit, and change from baseline to each post-baseline 
visit, by treatment group. Study baseline as defined in Section 10.2 will be used. 
Potentially clinically significant (PCS) post-baseline vital signs can be identified using the criteria shown in 
Table 10 below. The number and percentage of subjects with any post-baseline treatment-emergent 
potentially clinically significant vital sign value will be tabulated by treatment group for each criterion. Any 
subject with a post-baseline result meeting the criteria, including those collected at unscheduled visits, will 
be counted.  
Table 10 PCS Criteria for Vital Signs 
Parameter 
Criteria 
Heart Rate 
• 
≤ 50 bpm and decrease ≥ 15 bpm 
• 
≥ 100 bpm and increase ≥ 15 bpm 
• 
≥ 120 bpm and increase ≥ 15 bpm 
SBP 
• 
≤ 90 and decrease ≥ 20 mm Hg 
• 
< 140 mmHg and Increase ≥ 20 mmHg 
• 
≥ 140 mmHg and Increase ≥ 20 mmHg 
• 
≥ 160 mmHg and increase ≥ 20 mmHg 


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DBP 
• 
< 100 mmHg and Increase ≥ 20 mmHg 
• 
≥ 100 mmHg and Increase ≥ 20 mmHg 
• 
≤50 mmHg and decrease ≥15 mmHg 
• 
≥100 mmHg and increase ≥15 mmHg 
 
A plot will be presented to show the pattern of the SBP and DBP values over time by treatment group. 
Mean and SE will be presented in the plot. Additionally, spaghetti plots for SBP and DBP values over time 
will be provided for individual subjects with 1) maximum post-baseline SBP increased ≥ 20 mmHg and 
SBP ≥ 150 mmHg and 2) maximum post-baseline DBP increased ≥ 20 mmHg and DBP ≥ 100 mmHg. A 
shift plot displaying shifts from Baseline heart rate ≤ 100 to maximum heart rate >100 post-Baseline will 
be provided for the safety analysis set. All vital signs will be presented in a data listing. All vital sign tables 
and listings will be reported on the Safety Analysis Set. 
13.5.8.4 12-lead ECGs 
The average of triplicates from 12-lead ECGs will be used to evaluate the change from baseline in ECG 
parameters (heart rate, PR interval, RR interval, QRS duration, QT interval, and QTcF interval). 
Descriptive statistics (N, mean, SD, median, Q1, Q3, minimum, and maximum) of ECG parameters will be 
presented for baseline, each post-baseline visit, and change from baseline to each post-baseline visit by 
treatment group. Study baseline defined in Section 10.2 will be used. At Baseline, Week 1 and Week 4, 
descriptive statistics will also be presented for change from pre-dose to post-dose. All measurements, 
including those during unscheduled visits, will be provided in data listings.  
The number and percentage of subjects whose QTcF values have met each of the criteria below, will be 
summarized by treatment group for baseline and post-baseline assessment. Unscheduled visit results, or 
any single result from the triplicates meeting criteria criterion will be included.  
Table 11 PCS Criteria for ECG 
Parameter 
Criteria 
QTcF Interval 
• 
> 450 msec for males 
• 
> 470 msec for females 
• 
> 500 msec for males and females 
QTcF Interval Increase 
from Baseline 
• 
≥ 30 msec 
• 
≥ 60 msec 
 
All ECG tables and listings will be reported using the safety analysis set. 
13.5.8.5 Physical Examinations 
All physical examination findings will be listed in by-subject listings on the Safety Analysis Set. No 
tabulation summaries will be provided.  
13.5.9 Pharmacokinetic Endpoints 
Data from subjects who experience emesis within the PK sampling duration of IMR-687 on Study Day 1 
or Week 4 visit, will be evaluated on a case-by-case basis for exclusion from concentration-time data and 
PK analysis descriptive summaries. The individual subject data will be listed. 
If a quantifiable pre-dose concentration of IMR-687 is detected on Study Day 1 and this concentration is 
greater than 5% of the corresponding Cmax, all subject data will be excluded from all concentration-time 
and PK analysis descriptive summaries but will be included in the subject data listings. 


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Any protocol deviations or AEs which could impact PK parameter estimates will be evaluated in 
consultation with the Sponsor for exclusion from concentration-time data and PK analysis descriptive 
summaries. All data that are excluded in this manner will be listed and the reason for exclusion noted. 
All plasma concentration-time data will be reported to the same number of significant figures as displayed 
in the bioanalytical data. Lambdaz will be reported up to 4 decimal places and time-related parameters 
(T1/2, Tmax, and Tlast) will be reported up to 3 decimal places. All other PK parameters will be reported 
to the same number of significant figures as displayed in the bioanalytical data. 
The concentration-time data from subjects with sparse PK sampling collected using the sampling 
schedule reflected in protocol version 4.0 (08 Apr 2021) will be summarized descriptively and included in 
subject listings and analyzed for population PK. Noncompartmental analysis will not be performed with 
the PK data collected from these subjects. The concentration-time data from subjects with PK sampling 
collected using the sampling schedule reflected in the prior protocol versions (up to version 3.0; 29 Jan 
2020) will be summarized descriptively and listed. The PK data from these latter subjects will be used for 
the estimation of PK parameters using noncompartmental analysis. All available PK data from this study 
will also be used to explore any relationship between IMR-687 exposure and clinical response, PD 
endpoints, or AEs, as data permit. These data will be analyzed together with PK data from other clinical 
studies for a population PK analysis, as appropriate. Population PK analysis and other exploratory PK/PD 
analyses are not within the scope of this SAP and will be detailed in a separate population PK analysis 
plan. 
No analysis visit windows will be applied for reporting of plasma concentration-time data and PK analysis, 
nominal visit times will be used (i.e., Study Day 1 or Week 4). 
13.5.9.1 Plasma Concentrations 
Plasma concentrations of below the limit of quantification (BLQ) will be set to 0.01 ng/mL in the 
computation of mean concentration values. Descriptive statistics (number of subjects, mean, geometric 
mean, SD, coefficient of variation (%CV), geometric %CV, median, minimum, and maximum) will be used 
to summarize the plasma concentrations by dose and by study visit (i.e., Study Day 1 and Week 4 Visit) 
at each scheduled timepoint. 
Linear and semi-logarithmic plots of the arithmetic mean (± SD) and geometric mean (± SD) plasma 
concentrations by scheduled sampling time will be provided by dose and by study visit. These plots will 
show time in hours. The plots will present all calculated means and will include a reference line for the 
lower limit of quantification (LLOQ). 
Linear and semi-logarithmic plots of the individual plasma concentration by scheduled sampling time will 
be provided by subject (one subject per page) and by study visit. These plots will show time in hours. 
Individual plots will use the BLQ handling procedure described below for “Plasma Pharmacokinetic 
Parameters”. 
All individual subject plasma concentration data will be listed. 
13.5.9.2 Plasma Pharmacokinetic Parameters 
Plasma PK parameters for IMR-687 will be estimated using noncompartmental methods with Phoenix® 
WinNonlin® Version 8.1 (Certara, USA). The PK parameters will be estimated from the concentration-
time profiles, and AUCs will be calculated using a linear up/log down method using actual sampling times. 
The apparent terminal elimination half-life, T1/2, where determinable, will be calculated as the natural log 
of 2 divided by the terminal phase rate constant, lambdaz. The number of data points included in the 
regression will be determined by visual inspection, but a minimum of 3 data points in the terminal phase, 
excluding Cmax, is required to estimate lambdaz. In order for lambdaz and lambdaz derived parameters 
(AUCinf, T1/2, Vz/F, CL/F (single dose), and Vz/F to be reported, the adjusted r2 value reported in Phoenix® 
WinNonlin® must be ≥0.80. 


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For the purposes of estimating the PK parameters, BLQ values will be set to zero prior to the first 
measurable concentration and set to missing thereafter, including embedded BLQs. Scheduled sampling 
times will be used for the interim analyses and actual sampling times will be used for the final analysis. 
Missing concentration-time data will be treated as missing except for the pre-dose plasma concentrations 
where a value of 0 will be imputed for Study Day 1 for the purposes of PK parameter estimation. Similarly 
for the Week 4 visit, missing concentration-time data will be treated as missing except for the pre-dose 
concentration following steady state dosing where the lowest concentration value over the dosing interval 
(Cmin) will be used for imputation purposes. In addition, subjects must have a 24-hour PK sample 
collected at Study Day 1 and Week 4 in order to be included in the evaluation of accumulation ratio 
(RAUC). No extrapolation of AUC0-24 for any missing 24-hour PK sample will be performed. 
For the final analysis, if the actual time is missing, the scheduled sampling time will be substituted and 
flagged. Subjects must have at least 4 consecutive non-zero post-dose plasma concentrations in order for 
their data to be considered evaluable. Profiles that do not meet this criterion will be flagged for exclusion. 
Descriptive statistics (number of subjects, mean, geometric mean, SD, %CV, geometric %CV, median, 
minimum, and maximum) will be used to summarize the PK parameters by dose, timepoint, and by study 
visit. Additional PK evaluations may be performed as needed. 
Ctrough concentrations for Study Day 1 and Week 4 will be summarized in tables along with Ctrough 
concentrations at Week 24 and Week 52. 
All individual subject PK parameters will be listed by subject ID and treatment group. 
The following PK parameters for IMR-687 may be computed, where feasible. Additional PK parameters 
may be determined: 
Table 12 PK Parameters for IMR-687 
Parameter 
Description 
Study Day 1 (Single Dose) 
Cmax 
Maximum plasma concentration post-dose. Observed peak analyte concentration obtained 
directly from the experimental data without interpolation, expressed in concentration units. 
Tmax 
Time to maximum plasma concentration post-dose. First observed time to reach peak analyte 
concentration obtained directly from the experimental data without interpolation, expressed in 
time units. 
Tlast 
Time of last measurable plasma concentration. 
Ctrough 
Concentration at the end of the dosing interval. 
AUClast 
Area under the concentration-time curve from time 0 to the last measurable concentration 
post-dose. 
AUCinf 
Area under the concentration-time curve from time 0 to infinity, calculated as AUClast + 
(Clast/Lambdaz). 
Lambdaz 
Apparent terminal elimination phase rate constant. 
T1/2 
Apparent terminal elimination half-life. 
CL/F 
Apparent total body clearance from oral administration, calculated as Dose/AUCinf. 
Vz/F 
Apparent volume of distribution from oral administration, calculated as Dose/lambdaz × AUCinf. 
Week 4 (Steady State) 
Cmax,ss 
Maximum plasma concentration post-dose at steady state. Observed peak analyte 
concentration obtained directly from the experimental data without interpolation, expressed in 
concentration units. 


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Parameter 
Description 
Tmax,ss 
Time to maximum plasma concentration post-dose at steady state. First observed time to 
reach peak analyte concentration obtained directly from the experimental data without 
interpolation, expressed in time units. 
Tlast 
Time of last measurable plasma concentration. 
Ctrough 
Concentration at the end of the dosing interval. 
AUC0-24 
Area under the concentration-time curve from time 0 to 24 hours post-dose. 
Lambdaz 
Apparent terminal elimination phase rate constant. 
CLss/F 
Apparent total body clearance from oral administration at steady state, calculated as 
Dose/AUC0-24. 
Vz/F 
Apparent volume of distribution from oral administration at steady state, calculated as 
Dose/lambdaz × AUC0-24 
RAUC 
Accumulation ratio, calculated as AUC0-24 (Week 4)/ AUClast (Study Day 1; AUClast t = 24 
hours). 
Clast = last observed measurable plasma concentration 
 
 


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 References 
Ataga et al N Engl J Med 2017;376:429-39. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell 
Disease. 
Edwards R, Telfair J, Cecil H, Lenoci J. Reliability and validity of a self-efficacy instrument 
specific to SCD. Behav Res Ther. 2000 Sep;38(9):951-63. 
Hanmer J, Dewitt B, Yu L, Tsevat J, Roberts M, Revicki D, et al. Cross-sectional validation of 
the PROMIS-Preference Scoring system. PLoS One. 2018 Jul;13(7):e0201093. 
Hanmer, Dewitt, The Development of a Preference-based Scoring System for PROMIS (PROPr): A 
Technical Report (v1.4). December 2017. 
Keller SD, Yang M, Treadwell MJ, Werner EM, Hassell KL. Patient reports of health outcome for adults 
living with sickle cell disease: development and testing of the ASCQ-Me item banks. 
Health Qual Life Outcomes. 2014 Aug;12:125. San Keller, Manshu Yang, Christian Evensen, Tamika 
Cowans, American Institutes for Research. ASCQ-ME User’s Manual. December 2017. 
Sickle Cell Disease Self-Efficacy Scale Data Collection Worksheet. 
https://www.phenxtoolkit.org/protocols/view/820401. 
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for Industry, 
E3 Structure and Content of Clinical Study Reports, Questions and Answers (R1). 
 
 
 


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 Glossary of Abbreviations 
Glossary of Abbreviations: 
ACS 
Acute Chest Syndrome 
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
ASCQ-Me 
Adult Sickle Cell Quality of Life Measurement Information System 
AR1 
Auto-regressive-1 covariance matrix 
ATC 
Anatomic Therapeutic Classification 
AUC0-24 
Area Under the Concentration-Time Curve from Time 0 to 24 Hours Post-dose 
AUCinf 
Area Under the Concentration-Time Curve from Time 0 to Infinity 
AUClast 
Area Under the Concentration-Time curve from Time 0 to the Last Measurable 
Concentration Post-dose 
BLQ 
Below the Limit of Quantification 
CI 
Confidence Interval 
Clast 
Last Observed Measurable Plasma Concentration 
CL/F 
Apparent Total Body Clearance from Oral Administration after Single Dose 
CLss/F 
Apparent Total Body Clearance from Oral Administration at Steady State 
Cmax 
Maximum Plasma Concentration Post-dose after Single Dose 
Cmax,ss 
Maximum Plasma Concentration Post-dose at Steady State 
Cmin 
Minimum Plasma Concentration over the Dosing Interval 
Ctrough 
Concentration at the End of the Dosing Interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CS 
Compound symmetric covariance matrix 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
Hb 
Hemoglobin 
HbF 
Fetal Hemoglobin 
HU 
Hydroxyurea 
IA 
Interim Analysis 
Lambdaz 
Apparent Terminal Elimination Phase Rate Constant 
mITT 
Modified intent-to-treat 
IRT 
Interactive Response Technology 
IXRS/IVRS 
Interactive Voice Response System 


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Glossary of Abbreviations: 
J2R 
Jump to Reference 
LLOQ 
Lower Limit of Quantification 
LSMean 
Least squares mean 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing not at Random 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PROMIS 
Patient-Reported Outcomes Measurements Information System 
PT 
Preferred Term 
QD 
Once Daily 
QoL 
Quality of Life 
RAUC 
Accumulation Ratio using AUC0-24 data 
RBC 
Red Blood Cells 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SCD 
Sickle Cell Disease 
SCSES 
Sickle Cell Self-Efficacy Scale 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
International System of Units 
SOC 
System Organ Class 
T1/2 
Apparent Terminal Elimination Half-life 
Tlast 
Time of Last Measurable Plasma Concentration 
Tmax 
Time to Maximum Plasma Concentration after Single Dose 
Tmax,ss 
Time to Maximum Plasma Concentration at Steady State 
TEAE 
Treatment-Emergent Adverse Event 
VOC 
Vaso-Occlusive Event 
Vz/F 
Apparent Total Body Clearance from Oral Administration after Single Dose or 
Steady State 
WBC 
White Blood Cells 


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 Appendices 
Appendix 1 ACSQ-Me Scoring Tables 
 
 


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Appendix 2 PROMIS-29+2 Profile v2.1 (PROPr) Scoring Tables 
 
 
 


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Note: No conversion to T-score for Pain Intensity (0 -10).  


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Appendix 3 Schedule of Assessments 
 


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Abbreviations: AE = adverse event; ASCQ-Me = Adult Sickle Cell Quality of Life Measurement Information System; BP = blood pressure; CV = cardiovascular; 
ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; ET = early termination; F-cells = cells positive for HbF; HbF = fetal hemoglobin; HBsAg 
= hepatitis B surface antigen; HCV = hepatitis C virus; HR = heart rate; HU = hydroxyurea; ICAM-1 = intercellular adhesion molecule 1; IgM = immunoglobulin M; 


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MPO = myeloperoxidase; NA = not applicable; PD = pharmacodynamic; PE = physical examination; PK = pharmacokinetics; Pr:Cr = protein-to-creatinine (ratio); 
PROPr = Patient-Reported Outcomes Measurements Information System – Preference; qd = once daily; QoL = quality of life; SCSES = Sickle Cell Self-Efficacy 
Scale; TEAE = treatment-emergent adverse event; VCAM-1 = vascular cell adhesion molecule 1. 
Note: Unscheduled visits may occur, limited to visits resulting from potential TEAEs, drug dispensation, or other urgent study-related procedures. 
a Day 1 assessments should be performed prior to study drug administration. 
b All inclusion and exclusion criteria will be assessed at the Screening Visit; continued eligibility based on these criteria will be confirmed on Day 1. 
c Qualified site personnel will contact the subject at Week 2 and Week 6 to capture potential TEAEs and concomitant medications. Subjects will also be reminded 
of compliance with drug and the next visit schedule. If any AEs of significant clinical concern are identified during the telephonic visit, the subject will be 
requested to come into the site to be assessed. 
d Vital signs include HR, respiratory rate, BP, and body temperature and should be consistently measured in either the sitting or semi-supine position. At the Day 1 
and Week 4 visits, vital signs will be taken pre-dose and 2 hours (±20 minutes) post-dose, during the PK assessments. At all other timepoints, vital signs can be 
taken irrespective of taking study drug. 
e Complete PEs will be performed at Screening and at Weeks 12, 24, 36, 52, and 56; these consist of a general examination of the body, including the abdomen, 
heart, lungs, lymph nodes, back/neck, neurological system, skin, extremities, head, eyes, nose, and throat. At all other visits, symptom-directed PEs will be 
obtained after identification of AEs deemed by the investigator to be of significant clinical concern. 
f All ECGs to be performed in triplicate. At the Baseline, Week 1, and Week 4 visits, ECGs will be obtained pre-dose and 2 hours (±30 minutes) post-dose. At all 
other timepoints, ECG will be taken pre-dose. 
g Females of childbearing potential only. A serum pregnancy test will be performed during screening via a central laboratory. All subsequent pregnancy tests will 
be urine pregnancy tests performed locally (with test kits provided by the central laboratory). If a urine pregnancy test is positive, the result must be confirmed 
with a serum pregnancy test. 
h Serum virology (screening assessment) will be conducted only if clinically indicated. Testing will be performed through a central laboratory and may include 
HBsAg, hepatitis A IgM, and HCV antibody.  
i AEs and concomitant medications, including opioids and HU use, will be recorded at each visit throughout the study from screening through the EOS (Week 56) 
follow-up. 
j Includes HbF and % F-cells. Blood samples should be obtained prior to administration of study drug. 
k PD biomarkers that are not already assessed as part of standard hematology or serum chemistry testing may include, but are not limited to, the following: soluble 
E-selectin, P-selectin, ICAM-1, VCAM-1, and MPO. 
l QoL assessments include the specified components of the ASCQ-Me®, PROPr, SCSES. The translated QoL assessments from PROPr will be used when 
available. 
m At the Day 1 and Week 4 visits, serial blood samples for IMR-687 (including metabolites and HU, if applicable) plasma concentrations will be drawn pre-dose 
(within 30 minutes) and at 15 minutes (±5 minutes), 30 minutes (±5 minutes), and 3 hours (±20 minutes) after administration of study drug. A trough blood 
sample will be drawn pre-dose at Week 24 and on the last day of dosing (Week 52). The date/time of the last administered dose will be recorded. Patients 
dosed prior to protocol version 4.0 (08 Apr 2021) used the following PK sampling schedule: At the Day 1 and Week 4 visits serial blood samples for IMR-687 
plasma concentrations were drawn pre-dose (within 30 minutes) and at 30 minutes (±5 minutes), 1.5 hours (±15 minutes), 6 hours (±1 hour), and 24 hours (±2 
hours) after administration of study drug. On these full profile PK days, food details were also recorded at the study sites. A trough blood sample was drawn pre-
dose at Week 24 and on the last day of dosing (Week 52).  
n Each study drug bottle will contain 84 tablets. The indicated visits will require 2 bottles to be dispensed. 
o On days when study drug is taken in the clinic, food details will also be recorded. 
 


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Appendix 4 Data Handling Rules 
 
Category 
 
Description 
 
Data Handling Rule 
 
1. Age (years) 
Age (years) 
Age is collected from Demographics CRF page. 
2. First Dose 
Date/Time of 
Study Drug  
date/time of first dose of 
study drug 
The date and time (24 hr. clock) of the first dose of 
study drug will be taken from the Study Drug 
Administration CRF.  
3. Last Dose Date 
of Study Drug  
date of last dose of study 
drug 
The date of the last dose of study drug will be the 
Date of last dose from the End of Treatment CRF. 
 
If it is missing for the IA, and DMC analyses, use 
the data cutoff date. 
 
If it is missing at the database lock, the date of the 
last dose of study drug will be imputed as the later 
of last visit date, last dispensing date (from Drug 
Accountability CRF), date of 
Completion/Discontinuation, and death date. 
 
4. Last Visit Date 
Date of Last Visit 
Date of last visit according to the Clinic Visit and 
Telephone CRF. 
5. Last Study 
Participation 
Date (STDM 
variable, 
typically named 
RFPENDTC) 
Last Study Participation 
Date (STDM variable, 
RFPENDTC), where 
SDTM denotes Study 
Data Tabulation Model 
Last study participation date is defined as last 
known date of contact which would be the later of 
the following dates: last visit date, date of the last 
dose, date of Completion/Discontinuation, date of 
clinical study follow-up, or death date. 
6. Study Day 
Definitions 
Study Day for an 
assessment/event which 
occurred on or after the 
start of study drug 
Study Day = Date of assessment/event – date of 
the first dose of study drug + 1. 
Study Day for an 
assessment/event which 
occurred on a day prior to 
the first dose of study 
drug in the study 
Study Day = date of assessment/event – first dose 
date of study drug in the study. 
Study Day of 
Randomization 
Study Day of Randomization = date of 
randomization – date of the first dose of study drug 
in the study + 1. Study Day is 1 if baseline day is 
on the day of randomization. 
First Dose Day 
First Dose Day in the study is defined as the study 
day of the first dose of study drug in the study 
(Study Day 1). 
Last Dose Day 
Last Dose Day in the study is defined as the study 
day of the last dose of study drug in the study. 
7. Duration of an 
event  
The duration of any event  The duration of an event is defined as (stop date – 
start date + 1). 
8. Multiple 
assessments 
for the same 
visit 
Vital Sign, ECG and 
Laboratory assessments 
• 
All ECG assessments are to be performed in 
triplicate. Valid assessments will be averaged 
to get the analysis value for that visit. 


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Category 
 
Description 
 
Data Handling Rule 
 
• 
Other than for ECG assessments, the last 
non-missing measurement taken prior to the 
date/time of first study drug (including 
unscheduled assessments) will be the analysis 
baseline.  
• 
Windowing will be applied for by-visit analyses. 
Unscheduled or Screening visits that occurred 
before the Baseline visit will not be assigned 
an analysis visit. The early discontinuation visit 
will be eligible for allocation to an analysis visit.  
• 
If one or more results for a variable are 
assigned to the same analysis visit, the result 
with the date closest to the protocol scheduled 
day will be used in the analysis. If 
2 measurements in the same analysis visit 
window are equidistant from the protocol 
scheduled study day, the earliest measurement 
will be used in the analysis.  
• 
If multiple assessments are available on the 
same day (or for the same time point for ECG 
assessments), then the average of the 
assessments will be used in the analysis.  
• 
If both central and local assessments of the 
same lab test are available on the same day, 
the central result will take precedence over the 
local result. 
• 
All data will be listed in data listings. 
 
9. 
Special Lab 
Value 
Handling  
Lab values with a prefix 
such as: ‘>’, ‘<’, ‘+’ and 
‘Less than’ Etc. 
 
• 
‘>’: use the available original value +0.001 in 
the analyses. 
• 
‘<’: use the available original value –0.001 in 
the analyses. 
• 
‘+’: use the available original value without the 
prefix in the analyses. 
• 
‘≥’: use the available original value in the 
analyses. 
• 
‘≤’: use the available original value in the 
analyses. 
10. Prior and 
concomitant, 
medication / 
treatment 
Prior, concomitant, and 
post-treatment 
medication/treatment 
• 
Any medication that was used at any time prior 
to the date of first study drug is a Prior 
Medication. 
• 
Any medication that was used at any time on 
or after the date of first study drug and within 
30 days of the last dose of study drug is a 
Concomitant Medication.  
• 
If the date of first study medication is missing, 
then the date of randomization is used (as long 
as the subject is known to have received study 


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Category 
 
Description 
 
Data Handling Rule 
 
drug on at least one day during the study). 
Otherwise, in the case of missing dates, any 
period (Prior and Concomitant) that is possible 
based on the available information should be 
applied. 
11. Adverse event 
Missing CTCAE severity 
(toxicity grade) 
An AE with missing CTCAE severity grade will not 
be imputed. 
Missing relationship to 
study drug 
An AE with a missing relationship to study drug will 
not be imputed. 
Treatment-emergent 
adverse event  
An adverse event is considered treatment-
emergent if emerges on or after initiation of study 
drug, or an AE that existed pre-treatment and 
worsened in severity on or after initiation of study 
drug, through 30 days after the last dose of study 
drug. 
 
An adverse event that begins on the same date as 
the first dose of study drug is treatment-emergent if 
the AE begins after the time of first dose or if the 
time of AE onset is unknown.  
 
If the AE start date is partial/missing, then 
• 
If AE start date is completely missing, then the 
AE is considered as treatment-emergent. 
• 
If both AE start month and day are missing and 
AE start year is the same or after the first dose 
year, then the AE is considered as treatment-
emergent. 
• 
If AE start day is missing and AE start year and 
month are the same or after the first dose year 
and month, then the AE is considered as 
treatment-emergent. 
 
Missing/incomplete (partial) AE start and end dates 
will not be imputed for data listings. 
12. Treatment 
Duration 
(days) 
Treatment Duration 
(days) 
Treatment duration is defined as Date of last dose 
of a study drug - Date of first dose of a study drug 
+1.  
13. Duration of 
Exposure 
(days) 
Duration of Exposure 
(days) 
Exposure is defined as (Date of the last dose of the 
study drug – Date of first dose of the study drug + 
1).  
14. General 
Conversion of Duration in 
Days to Duration in 
Years/Months 
Duration in Years = Duration in Days/365.25 
 
Duration in Month = Duration in Days/30.4375 
 
15. Hard coding 
Hard coding for data 
analysis 
Hard Coding is not allowed during data analysis 
unless if agreed in writing by Imara. 
 
 


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Appendix 5 CTCAE Grade Criteria for Selected Hematology and 
Chemistry parameters 
 
Investigations 
Grade 
Laboratory 
Analyte 
1 
2 
3 
4 
aPTT (activated 
partial 
thromboplastin 
time) prolonged 
>ULN - 1.5 x ULN 
>1.5 – 2.5 x ULN 
>2.5 x ULN 
- 
Alanine 
aminotransferase 
increased 
>ULN – 3.0 x ULN 
if baseline was 
normal; 1.5 - 3.0 x 
baseline if baseline 
was abnormal  
 
>3.0 – 5.0 x ULN if 
baseline was 
normal; >3.0 - 5.0 
x baseline if 
baseline was 
abnormal  
 
>5.0 – 20.0 x ULN 
if baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal  
 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal  
 
Alkaline 
phosphatase 
increased 
>ULN – 2.5 x ULN 
if baseline was 
normal; 2.0 - 2.5 x 
baseline if 
baseline was 
abnormal  
 
>2.5 – 5.0 x ULN if 
baseline was 
normal; >2.5 - 5.0 
x baseline if 
baseline was 
abnormal  
 
>5.0 – 20.0 x ULN 
if baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal  
 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal  
 
Aspartate 
aminotransferase 
increased 
>ULN – 3.0 x ULN 
if baseline was 
normal; 1.5 - 3.0 x 
baseline if 
baseline was 
abnormal  
 
>3.0 – 5.0 x ULN if 
baseline was 
normal; >3.0 - 5.0 
x baseline if 
baseline was 
abnormal  
 
>5.0 – 20.0 x ULN 
if baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal  
 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal  
 
Blood bilirubin 
increased 
>ULN – 1.5 x ULN 
if baseline was 
normal; > 1.0 - 1.5 
x baseline if 
baseline was 
abnormal  
 
>1.5 – 3.0 x ULN if 
baseline was 
normal; >1.5 - 3.0 
x baseline if 
baseline was 
abnormal  
 
>3.0 – 10.0 x ULN 
if baseline was 
normal; >3.0 - 
10.0 x baseline if 
baseline was 
abnormal  
 
>10.0 x ULN if 
baseline was 
normal; >10.0 x 
baseline if 
baseline was 
abnormal  
 
Creatinine 
increased 
>ULN -1.5 x ULN 
>1.5 – 3.0 x 
baseline; >1.5 -3.0 
x ULN 
>3.0 baseline; 
>3.0 – 6.0 x ULN 
>6.0 x ULN 


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Investigations 
Grade 
Laboratory 
Analyte 
1 
2 
3 
4 
GGT (gamma-
glutamyl 
transferase) 
increased 
>ULN – 2.5 x ULN 
if baseline was 
normal; 2.0 - 2.5 x 
baseline if 
baseline was 
abnormal  
 
>2.5 – 5.0 x ULN if 
baseline was 
normal; >2.5 - 5.0 
x baseline if 
baseline was 
abnormal  
 
>5.0 – 20.0 x ULN 
if baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal  
 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal  
 
Blood bicarbonate 
decreased 
<LLN and no 
intervention 
initiated 
 
 
 
Blood lactate 
dehydrogenase 
increased 
>ULN 
 
 
 
Hemoglobin 
increased (a) 
Increase in >0 – 2 
gm/dL above ULN 
(a) 
Increase in >2 – 4 
gm/dL above ULN 
(a) 
Increase in >4 
gm/dL above ULN 
(a) 
n/a 
Anemia 
(hemoglobin 
decreased) 
LLN- 10g/dL;  
<LLN – 6.2 
mmol/L; <LLN – 
100 g/L 
<10.0 – 8.0 g/dL;  
<6.2 – 4.9 mmol/L;  
<100 – 80g/L 
<8.0 g/dL; <4.9 
mmol/L; <80 g/L; 
transfusion 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
INR increased 
>1.2 – 1.5; >1 -1.5 
x baseline if on 
anticoagulation 
(use of 
anticoagulation 
identified using the 
B01A ATC code) 
>1.5 – 2.5; >1.5 – 
2.5 x baseline if on 
anticoagulation 
(use of 
anticoagulation 
identified using the 
B01A ATC code) 
>2.5; >2.5 x 
baseline if on 
anticoagulation 
(use of 
anticoagulation 
identified using the 
B01A ATC code) 
- 
Eosinophilia 
>ULN and 
>Baseline 
 
Steroids initiated 
 
Neutrophil count 
decreased 
<LLN - 1500/mm3; 
<LLN - 1.5 x 10e9 
/L 
<1500 - 
1000/mm3; <1.5 - 
1.0 x 10e9 /L 
<1000 - 500/mm3; 
<1.0 - 0.5 x 10e9 
/L 
<500/mm3; <0.5 x 
10e9 /L 
Lymphocyte count 
decreased 
<LLN - 800/mm3; 
<LLN - 0.8 x 
10e9/L 
<800 - 500/mm3; 
<0.8 - 0.5 x 10e9 
/L 
<500 - 200/mm3; 
<0.5 - 0.2 x 10e9 
/L 
<200/mm3; <0.2 x 
10e9 /L 
Lymphocyte count 
increased 
 - 
>4000/mm3 - 
20,000/mm3 
>20,000/mm3 
 - 


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Investigations 
Grade 
Laboratory 
Analyte 
1 
2 
3 
4 
Leukocytosis 
(White blood cell 
increased)  
 
 
>100,000/mm3 
Clinical 
manifestations of 
leucostasis (sic); 
urgent intervention 
indicated 
 
Note that the 
spelling is often 
“leukostasis” in the 
literature. 
Platelet count 
decreased 
<LLN - 
75,000/mm3;  
<LLN - 75.0 x 
109/L 
<75,000 - 
50,000/mm3;  
<75.0 - 50.0 x 
109/L 
<50,000 - 
25,000/mm3; 
<50.0 - 25.0 x 
109/L 
<25,000/mm3; 
 <25.0 x 109/L 
White blood cell 
decreased 
<LLN – 3000/mm3; 
<LLN – 3.0 x 109/L 
<3000 – 
2000/mm3; 
 <3.0 – 2.0 x 109 /L 
<2000 – 
1000/mm3; <2.0 – 
1.0 x 109 /L 
<1000/mm3;  
<1.0 x 109 /L 
(a) Definition: A finding based on laboratory test results that indicate increased levels of hemoglobin 
above normal – i.e. above ULN. 
 


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Metabolism and Nutrition Disorders 
 
Grade 
Adverse Event 
1 
2 
3 
4 
Hypercalcemia 
(Calcium Increased) 
Corrected serum 
calcium of >ULN - 
11.5 mg/dL; >ULN 
- 2.9 mmol/L; 
Ionized calcium 
>ULN - 1.5 
mmol/L 
Corrected serum 
calcium of >11.5 - 
12.5 mg/dL; >2.9 - 
3.1 mmol/L; 
Ionized calcium 
>1.5 - 1.6 mmol/L; 
symptomatic 
Corrected serum 
calcium of >12.5 - 
13.5 mg/dL; >3.1 - 
3.4 mmol/L; 
Ionized calcium 
>1.6 - 1.8 mmol/L; 
hospitalization 
indicated 
Corrected serum 
calcium of >13.5 
mg/dL; >3.4 
mmol/L; Ionized 
calcium >1.8 
mmol/L; life-
threatening 
consequences 
Hyperkalemia 
(Potassium 
Increased) 
>ULN - 5.5 
mmol/L 
>5.5 - 6.0 mmol/L; 
intervention 
initiated 
>6.0 - 7.0 mmol/L; 
hospitalization 
indicated 
>7.0 mmol/L; life-
threatening 
consequences 
Hypermagnesemia 
(Magnesium 
Increased) 
>ULN - 3.0 
mg/dL; >ULN - 
1.23 mmol/L 
n/a 
>3.0 - 8.0 mg/dL; 
>1.23 - 3.30 
mmol/L 
>8.0 mg/dL; >3.30 
mmol/L; life-
threatening 
consequences 
Hypernatremia 
(Sodium Increased) 
>ULN - 150 
mmol/L 
>150 - 155 
mmol/L; 
intervention 
initiated 
>155 - 160 
mmol/L; 
hospitalization 
indicated 
>160 mmol/L; life-
threatening 
consequences 
Hypoalbuminemia 
(Albumin 
Decreased) 
<LLN - 3 g/dL; 
<LLN - 30 g/L 
<3 - 2 g/dL; <30 - 
20 g/L 
<2 g/dL; <20 g/L 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Hypocalcemia 
(Calcium 
Decreased) 
Corrected serum 
calcium of <LLN - 
8.0 mg/dL; <LLN - 
2.0 mmol/L; 
Ionized 
calcium<LLN - 1.0 
mmol/L 
Corrected serum 
calcium of  <8.0 - 
7.0 mg/dL; <2.0 - 
1.75 mmol/L; 
Ionized calcium 
<1.0- 0.9 mmol/L; 
symptomatic 
Corrected serum 
calcium of  <7.0 - 
6.0 mg/dL; <1.75 - 
1.5 mmol/L; 
Ionized calcium 
<0.9- 0.8 mmol/L; 
hospitalization 
indicated 
Corrected serum 
calcium of <6.0 
mg/dL; <1.5 
mmol/L;Ionized 
calcium <0.8 
mmol/L;life-
threatening 
consequences 
Hypoglycemia 
(Glucose 
Decreased) 
<LLN - 55 mg/dL; 
<LLN - 3.0 
mmol/L 
<55 - 40 mg/dL; 
<3.0 - 2.2 mmol/L 
<40 - 30 mg/dL; 
<2.2 - 1.7 mmol/L 
<30 mg/dL; <1.7 
mmol/L; life-
threatening 
consequences; 
seizures 
Hypokalemia 
(Potassium 
Decreased) 
<LLN - 3.0 
mmol/L 
Symptomatic with 
<LLN - 3.0 
mmol/L; 
intervention 
indicated 
<3.0 - 2.5 mmol/L; 
hospitalization 
indicated 
<2.5 mmol/L; life-
threatening 
consequences 
Hypomagnesemia 
(Magnesium 
Decreased) 
<LLN - 1.2 mg/dL; 
<LLN - 0.5 
mmol/L 
<1.2 - 0.9 mg/dL; 
<0.5 - 0.4 mmol/L 
<0.9 - 0.7 mg/dL; 
<0.4 - 0.3 mmol/L 
<0.7 mg/dL; <0.3 
mmol/L; life-
threatening 
consequences 
Hyponatremia 
(Sodium 
Decreased) 
<LLN - 130 
mmol/L 
125-129 mmol/L 
and asymptomatic 
125-129 mmol/L 
symptomatic; 120-
124 mmol/L 
<120 mmol/L; life-
threatening 
consequences 


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Metabolism and Nutrition Disorders 
 
Grade 
Adverse Event 
1 
2 
3 
4 
regardless of 
symptoms 
 
Renal and Urinary 
Disorders 
 
 
Grade 
Adverse Event 
1 
2 
3 
4 
Chronic kidney 
disease 
eGFR (estimated 
Glomerular 
Filtration Rate) or 
CrCl (creatinine 
clearance) <LLN -
60 ml/min/1.73 m2 
or proteinuria 2+ 
present; urine 
protein/creatinine 
>0.5 
eGFR or CrCl 59 - 
30 ml/min/1.73 m2 
eGFR or CrCl 29 - 
15 ml/min/1.73 m2 
eGFR or CrCl <15 
ml/min/1.73 m2; 
dialysis or renal 
transplant 
indicated 
 
 
 
 


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Appendix 6 SAS Codes for Statistical Analysis 
Test 
Template SAS Code for Modeling (SAS Version 9.4) 
Determination 
of lower 
O’Brien-
Fleming 
stopping 
boundary for 
the primary 
efficacy 
endpoint at 
the interim 
analysis  
Proc Seqdesign errspend plots=all boundaryscale=pvalue; 
     PrimaryEfficacy: 
       design 
       alpha = 0.05 
       beta = 0.20 
       alt = twosided /* two-sided test*/ 
       nstages = 2 
       method (reject)= errfuncobf /* O’Brien-Fleming as implemented by Lan- 
        DeMets */ 
       info = cum(24 52) /* information proportion are based on 24 wks out of 52 wks*/; 
run; 
Primary 
Analysis: 
Stratified 
Wilcoxon 
rank-sum test  
proc npar1way data=ITT; 
Title ‘Primary Endpoint – Comparison of Annualized VOC Rates’; 
Title2 ‘Intent To Treat Population’;  
  class TRT;     
  var ARVOC;  
  strata <stratification factors: REGION HU >; 
run; 
Negative 
binomial 
regression 
proc genmod data=ITT; 
Title ‘Sensitivity Analysis for Primary Endpoint – Negative Binomial Regression’; 
  class TRT <stratification factors: REGION HU >; *TRT is treatment group; 
  model Y = TRT <stratification factors: REGION HU> / dist = negbin link = log offset = 
LTIME;   *Y is the count of VOC, LTIME is the log of exposure time in years; 
lsmeans TRT / cl diff exp;  
 
Time to Event 
Analysis  
proc lifetest data=ITT plots=(survival(nocensor atrisk cb));  
Title ‘Secondary Endpoint – Time to Event Analysis Time to first VOC’; 
  time TIME*VOC(0); 
  Strat TRT; 
run; 
Mixed model 
repeated 
measures 
(MMRM)  
proc mixed data=ITT; 
  class SUBJECT TRT VISIT HU REGION; 
  model CFB = TRT VISIT TRT*VISIT BASELINE HU REGION; *CFB=change from 
baseline; 
  repeated VISIT/ TYPE = UN ddfm=kr sub=SUBJECT; /*Type=CS and then Type   
AR(1) will be used if UN does not work*/ 
  lsmeans TRT*VISIT/cl diff alpha=0.05; 
  lsmeans TRT/cl diff alpha=0.05; 
run; 
 
 
Multiple 
Imputation for 
the annualized 
rate of VOCs 
proc mi; 
   class TRT REGION HU ; 
   fcs reg(AVOC = TRT REGION HU VOC_O DUR); *AVOC= annualized VOC rate;     
VOC_O   =Number of observed VOCs; DUR = Duration in the study.   
run; 
 


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Test 
Template SAS Code for Modeling (SAS Version 9.4) 
with FCS 
Method 
Negative 
binomial 
regression 
based on 
Multiple 
Imputed 
dataset 
proc genmod data=MIDATA; 
   by _imputation_;  
   class TRT REGION HU ; *TRT is treatment group; 
   model Y = TRT REGION HU / dist = negbin link = log offset = LTIME;    
  *Y is the  count of VOC, LTIME is the log of exposure time in years; 
    lsmeans TRT / cl diff exp;  
run; 
 
Combine 
Parameter 
Estimates  
proc mianalyze data=outreg; 
   modeleffects TRT; /*TRT is the variable for mean treatment differences*/ 
   stderr TRTERR; /*TRTERR is the standard errors for treatment differences*/ 
run; 
 


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Appendix 7 Power Calculation for the Primary Endpoint (Annualized 
Rate of VOCs) 
 
 
 
Appendix 8 Mock-up Tables, Listings, and Figures 
 
Mock-up tables, listings, and figures are presented in a separate document.