Clinical trial NCT02092909
Conditions: Waldenstrom's Macroglobulinemia
Sponsor: Idera Pharmaceuticals, Inc.
Start date: 2014-03-01; Completion date: 2017-11-01
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in approximately 90% of the patients with Waldenström's macroglobulinemia. MYD88 is a key linker protein in the signaling pathway of Toll Like Receptors (TLRs) 7, 8, and 9, and IMO-8400 is an oligonucleotide specifically designed to inhibit TLRs 7,8, and 9. The scientific hypothesis for use of IMO-8400 to treat patients with Waldenström's macroglobulinemia depends on the inhibition of mutant MYD88 signaling in the TLR pathway, thereby interrupting the proliferation of cell populations responsible for the propagation of the disease.

Detailed description:
Eligible subjects will be enrolled and assigned to escalating dose cohorts. Treatment will be administered by subcutaneous injection.

Arms: arm 1: IMO-8400 at escalating dose levels by subcutaneous injection
Interventions: intervention 1: IMO-8400
Intervention descriptions: intervention 1: IMO-8400 at escalating dose levels by subcutaneous injection

Protocol documents:
Prot_000.pdf: 
IMO-8400 
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 PROTOCOL 8400-401 
 
Study Title 
Phase 1/2 Open-label, Multiple-dose, Dose-escalation Study to 
Evaluate the Safety and Tolerability of IMO-8400 in Patients with 
Relapsed or Refractory Waldenström’s Macroglobulinemia 
Investigational Drug: 
IMO-8400 
FDA IND: 
119651 
Sponsor: 
Idera Pharmaceuticals, Inc. 
167 Sidney Street  
Cambridge, MA 02139 
Protocol Number: 
8400-401  
Protocol Version: 
7.0 
Date: 
14 March 2016 
 
 
 
 
 
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This document contains Idera Pharmaceuticals’ privileged or confidential information and is 
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you, your staff and applicable institutional review board(s). The information is not to be 
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Contact Information  
Any serious adverse event (SAE) must be reported within 24 hours. 
See Section 10.5 for detailed reporting procedures. 
 
Table-1.  
Emergency and Pharmacovigilance Contacts 
Role in Study 
Name, Title, Address 
Telephone and Email 
24-Hour Emergency 
Contact 
Mark Cornfeld MD, MPH 
Vice President & Medical Lead, Oncology 
Idera Pharmaceuticals, Inc. 
505 Eagleview Blvd., Suite 212 
Exton, PA 19341 
 
Office: +1 484 348 1629 
Cell: +1 609 240 7312 
email: mcornfeld@iderapharma.com 
Pharmacovigilance 
Contact 
Theresa Wehrle, RN 
Sr. Safety Specialist, Safety and 
Pharmacovigilance 
INC Research, LLC 
4800 Falls of the Neuse Road 
Raleigh, NC 27609 
Office: +1 919 926 5732 
email: twehrle@incresearch.com  
Table-2.  
Study Contact Information 
Role in Study 
Name, Title, Address 
Telephone and Email 
Responsible Physician 
Mark Cornfeld MD, MPH 
Vice President & Medical Lead, Oncology 
Idera Pharmaceuticals, Inc. 
505 Eagleview Blvd., Suite 212 
Exton, PA 19341 
 
Office: +1 484 348 1629 
Cell: +1 609 240 7312 
email: mcornfeld@iderapharma.com 
 
Clinical Trial Manager 
Lindsey Simov 
Idera Pharmaceuticals, Inc. 
167 Sidney Street 
Cambridge, MA 02139 
 
Office: +1 617 679 5533 
email: lsimov@iderapharma.com 
Medical Monitors 
Mark Cornfeld MD, MPH 
Vice President & Medical Lead, Oncology 
Idera Pharmaceuticals, Inc. 
505 Eagleview Blvd., Suite 212 
Exton, PA 19341 
 
Office: +1 484 348 1629 
Cell: +1 609 240 7312 
email: mcornfeld@iderapharma.com 
 
 
Joanna Horobin, MB, ChB 
Sr. Vice President, Chief Medical Officer 
Idera Pharmaceuticals, Inc. 
167 Sidney Street 
Cambridge, MA 02139 
 
Office: +1 617 679 5510 
Cell: +1 781 249 2166 
email: jhorobin@iderapharma.com  
Project Manager 
Nicole Pusey 
Project Manager, Early Phase Oncology 
INC Research, LLC 
3201 Beechleaf Ct., Suite 600 
Raleigh, NC 27609 
Office: +1 919 341 3302 
email: nicole.pusey@incresearch.com  
 
 
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1. 
SYNOPSIS 
1.1. 
Protocol Information 
Protocol Number 
8400-401 
Protocol Title 
Phase 1/2 Open-label, Multiple-dose, Dose-escalation Study to Evaluate the Safety 
and Tolerability of IMO-8400 in Patients with Relapsed or Refractory 
Waldenström’s Macroglobulinemia 
Sponsor 
Idera Pharmaceuticals, Inc. 
Name of Finished Product 
IMO-8400 for Injection, 150 mg 
Name of Active ingredient 
IMO-8400 
Phase of Development 
1/2  
Indication (Target) 
Relapsed or Refractory Waldenström’s Macroglobulinemia  
Number of Patients 
Approximately 60 patients in planned escalation and expansion cohorts; potential 
for additional patients in contingency cohorts or as replacements 
Number of Sites 
Multiple Centers in the US 
Date first patient enrolled  
Q2 2014 
Est. date last patient enrolled  
Q4 2016  
Est. date last patient last visit 
Q2 2017  
1.2. 
Objectives 
1.2.1. 
Primary Objective 
• To evaluate the safety and tolerability of escalating dose levels of IMO-8400 
administered by subcutaneous (SC) injection in patients with relapsed or refractory 
Waldenström’s Macroglobulinemia (WM).  
1.2.2. 
Secondary Objectives 
• To assess the treatment effect (clinical activity) of escalating dose levels of 
IMO-8400 using disease-specific international guidelines for classifying clinical 
response [1].  
• To identify an optimal dose of IMO-8400 for further clinical evaluation. 
• To characterize the pharmacokinetics (PK) of escalating dose levels of IMO-8400 
administered by SC injection.  
1.2.3. 
Exploratory Objectives 
• To investigate associations between the treatment effect of IMO-8400 and selected 
biomarkers (e.g., serum cytokines). 
• To correlate the presence of myeloid differentiation primary response gene (88) 
L265P mutation with clinical outcome. 
• To assess the potential immunogenicity of IMO-8400 administered by SC injection. 
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1.3. 
Study Design and Methodology 
1.3.1. 
Brief Background and Rationale 
IMO-8400 is a second-generation oligonucleotide antagonist of Toll-like receptors (TLR) 7, 8, 
and 9, which blocks immune activation mediated through those receptors.  In a Phase 1 study 
IMO-8400 was administered to healthy adults by SC injection at single-doses and multiple-doses 
(once weekly for 4 weeks) up to 0.6 mg/kg (see Section 4.4 for details).  All treatments were 
well-tolerated, with mild injection site reactions (ISRs) and no pattern of systemic reactions or 
laboratory changes.  
In recent studies, a high frequency of mutation in the signaling pathway downstream of TLR7, 8, 
and 9 has been identified in patients with B-cell malignancies, including more than 90% of 
patients with WM [2].  In vitro studies of B-cell tumor lines indicate that such mutations are 
associated with an increase in cell activation, proliferation, and survival [3], and that loss of 
endosomal TLRs results in markedly decreased cell proliferation and survival [4].  Data from 
Idera indicate that treatment of such cell lines with IMO-8400 has a similar effect (see 
Investigator’s Brochure for details).  
The current study represents the first clinical trial of IMO-8400 in patients with B-cell 
malignancy.  
1.3.2. 
Study Overview 
This is an open-label, multiple-dose, dose escalation study of IMO-8400 in patients with relapsed 
or refractory WM.  
1.3.3. 
Dose-escalation Cohorts 
The dose-escalation cohorts (3 to 6 patients each) will systematically evaluate the safety and 
tolerability of IMO-8400 at increasing dose levels in order to identify the maximum tolerated 
dose (MTD)/recommended Phase 2 dose (RP2D).  
• The planned dose escalation cohort levels for IMO-8400 are 0.6, 1.2, 2.4, and 
3.6 mg/kg administered once weekly and 1.2 mg/kg administered twice weekly 
(Table-3). Additional dose levels, schedules, and routes of administration may be 
evaluated based upon the emerging data. Weekly exposure is based on body weight 
(see Section 8.1 for details). Doses will be administered by SC injection.  
• For Dose Level 3 (refer to Table-3), the total dose will be divided into 2 equal 
portions (1.2 mg/kg twice weekly), administered as separate SC injections over the 
course of the week, preferably 72 to 96 hours apart (minimum 48 hours) (see 
Section 8.4 for details).  
• Once safety has been established for the 2.4 mg/kg/week as a divided weekly dose 
(1.2 mg/kg twice weekly), the same dose level of 2.4 mg/kg/week and subsequent 
dose levels will be given as a once weekly administration. 
• Once the RP2D/MTD has been established, patients being treated at lower dose levels 
may have their doses escalated to the RP2D/MTD upon discussion and agreement 
between the Sponsor and the Investigator.  
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Table-3. 
Planned Dose Escalation Cohorts 
Dose Level 
IMO-8400 Dose (mg/kg)  
Frequency 
Initial Cohort Size 
1 (starting dose) 
0.6 
Once Weekly 
3-6 
2 
1.2  
Once Weekly 
3-6 
3 
1.2 
Twice Weekly 
3-6 
4 
2.4 
Once Weekly 
3-6 
5 
3.6 
Once Weekly 
3-6 
1.3.4. 
Dose-escalation Procedures 
Procedures for patient safety are summarized below and presented in detail in the protocol 
sections indicated:  
• Explicit definitions for identifying suspected adverse reactions as dose-limiting 
toxicity (DLT) events (see Section 6.3.1 for details). 
• Explicit definition for MTD (see Section 6.3.2). 
• All injections of study medication will be administered by study personnel and all 
patients observed for 2 hours following the first injection (including the first injection 
of a new dose level in the case of intra-patient dose escalation) and for at least 30 min 
following all other injections.  
• Detailed provisions for management of study drug in individual patients based on 
safety, tolerability, and disease response (see Section 6.5).  
• Constitution of a Data Review Committee (DRC) comprised of the Idera Medical 
Monitor and Investigators from participating sites to decide whether to continue or 
halt dose escalation, or explore intermediate dose levels (Section 6.3.3). 
1.3.5. 
Dose-escalation Enrollment and Review 
Each dose-escalation cohort is expected to enroll at least 3 patients, with a maximum of 6.  
• If the initial 3 patients all complete 4 weeks of treatment without a DLT event, the 
DRC will conduct a dose-escalation review.  
• If 1 of the initial 3 patients experiences a DLT event prior to completing 4 weeks of 
treatment, then enrollment at that dose level will continue to a total of 6 patients and 
the dose-escalation review will be done when all 6 patients have completed 4 weeks 
treatment. 
• If 2 patients at a dose-level experience DLT events during the first 4 weeks of 
treatment, then no further patients will be enrolled until the DRC completes a review, 
which should be done as soon as feasible.  
The DRC review will include all safety data available for the cohort.  The following represent 
anticipated outcomes for the review process.  
• Dose escalation – progression to the next planned dose level.  
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• Continue cohort enrollment (applicable only to review after 3 patients) – enroll up to 
6 patients at the current dose level to obtain additional safety data for subsequent 
review. 
• Dose de-escalation – enrollment of intermediate dose levels for exploration of other 
schedules of administration (see Section 6.5.2).  
• Approve enrollment in an expansion cohort at a selected dose level, if applicable (see 
Section 1.3.6). 
• No further dose escalation enrollment – at this time the DRC will indicate the dose 
level that they consider represents the MTD.  
1.3.6. 
Expansion Cohorts 
The expansion cohorts provide for additional enrollment at agreed upon dose levels to assess the 
dose dependence of clinical response.   
Once the MTD or a potential RP2D and/or schedule have been established during dose 
escalation, up to 22 patients will be treated at the RP2D level according to this schedule.  The 
Sponsor may decide at any point during the expansion phase to modify the RP2D based on 
emerging data including, but not limited to, safety, DLTs, PK, and clinical activity.  If such a 
change is made, enrollment may continue at the selected dose level in up to 22 patients.  
1.3.7. 
Management of Study Treatment in Individual Patients 
Each enrolled patient will receive IMO-8400 at the assigned dose level until the earliest of: 
• Clinical DLT event – see Section 6.3.1.  
− Study treatment will be discontinued in patients determined to have a clinical 
DLT event until resolution and may only be resumed after discussion with an 
Idera Medical Monitor and agreement that it is in the patient’s best interest to 
continue. 
− For a dose modifying event (DME), provision is made for interrupting dosing for 
up to 3 weeks and, if the acute toxicity improves sufficiently, resuming treatment 
at a lower dose level based on discussion between the sponsor’s designated 
medical monitor and the treating physician. 
− For DLT laboratory events, provision is made for pausing treatment for up to 
3 weeks and, if the acute toxicity improves sufficiently, resuming treatment at a 
lower dose level (see Section 6.5.2 for details).  
− The Investigator will review with the Medical Monitor decisions to discontinue, 
pause, and/or restart study treatment. 
• Disease progression – based on scheduled assessments at Week 1 of each cycle.  
Unscheduled assessments may be conducted in response to new clinical observations.  
Disease status will be classified according to international guidelines [1] (see 
Section 9.5 for details).  
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• Termination of participation in the study – due to adverse event (AE), withdrawal of 
consent, intolerable toxicity, or loss to follow up.  
In certain instances, patients may be deriving clinical benefit despite objective signs of 
progressive disease such as radiologic progression.  It can be anticipated that based on the study 
drug’s mechanism of action, through an immunologic mediated effect, signs of radiologic 
response may be delayed.  Based on these considerations, continuing to treat some patients past 
progressive disease may be considered after discussion between the Sponsor and Investigator, 
provided the conditions in Section 6.5.1 are met. 
1.4. 
Study Structure  
• Screening will be done within 21 days prior to Day 1 (the first injection of study 
drug). See Section 9.2 for details of screening and Section 9.3 for details of the 
enrollment process.  
• Treatment is scheduled to be administered in 8-week cycles until progressive disease, 
unacceptable toxicity, withdrawal of consent, or end of study.  
• Assessments for treatment response (or disease progression) are scheduled every 
8 weeks ± 1 week (at the start of a new cycle) for clinical assessments (see 
Section 9.4.1), and every 4 weeks ± 1 week for laboratory assessments (see 
Section 9.4.2). 
• End-of-Treatment (EOT) visit will be performed within 5 days of the decision to 
terminate treatment.  
• End-of-Study (EOS) visit will be performed 30 to 35 days after the last dose of study 
drug.  
A detailed schedule of events is presented in Table-4.  
1.5. 
Diagnosis and Patient Selection Criteria  
1.5.1. 
Qualifying Disease 
To be eligible for this study, a patient must have WM meeting all of the following criteria:  
1. Primary diagnosis established according to criteria of the Second International Workshop 
on WM [5] (see Section 16.1).  
2. Has relapsed or progressed (“refractory”) based on the criteria for assessing response 
from the VIth International Workshop on WM [1] (see Section 9.5).  
3. Has, at Screening, serum monoclonal Immunoglobulin M protein ≥ 0.5 g/dL.  
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1.5.2. 
Inclusion Criteria 
To be eligible for this study, a patient must meet all of the following inclusion criteria: 
1. Be at least 18 years of age 
2. Have signed the current approved informed consent form 
3. Have an Eastern Cooperative Oncology Group Performance Status ≤ 2 
4. Patients must meet the following laboratory criteria 
- Hemoglobin ≥ 7.5 g/dL 
- Absolute neutrophil count ≥ 1.0 x 109/L (1000/mm3)  
- Platelets ≥ 50,000/μL  
- Serum creatinine ≤ 2.5 x the upper limit of normal (ULN)  
- Serum aspartate aminotransferase ≤ 2.5 x ULN  
- Serum alanine aminotransferase ≤ 2.5 x ULN  
- Total bilirubin ≤ 1.5 x ULN  
- Prothrombin time ≤ 1.5 x ULN 
5. Life expectancy > 3 months 
6. For women of childbearing potential and men, agree to use effective contraceptive 
methods from Screening, through the study, and for at least 4 weeks after the last dose of 
study drug.  Effective birth control (contraception) methods are defined as one of the 
following: 
– Abstinence  
– Condoms and spermicide  
– Diaphragm and spermicide  
– Oral or implanted hormonal contraceptive (e.g., Implanon™)  
– An intra-uterine device 
Non-childbearing potential is defined as a female who meets either of the following 
criteria:  
– Age ≥ 50 years and no menses for at least 3 years 
– Documented hysterectomy, bilateral tubal ligation, or bilateral oophorectomy 
7. For women of childbearing potential, have a negative serum pregnancy test at Screening  
8. Be willing and able to comply with this protocol 
1.5.3. 
Exclusion Criteria 
Patients with any of the following will be excluded from participation in the study: 
1. Has known hypersensitivity to any oligodeoxynucleotide 
2. Is nursing 
3. Has body mass index > 34.9 kg/m2 
4. Has an indeterminate or positive test for antibody to human immunodeficiency virus 
(HIV-1 or -2) or hepatitis C virus 
5. Has a positive test for hepatitis B surface antigen  
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6. Has known complement deficiency such as properdin deficiency or hereditary 
angioedema 
7. Is, at the initiation of study drug, receiving chronic systemic corticosteroid therapy 
> 20 mg of prednisone daily (or equivalent); steroids administered topically or by 
inhalation are permitted 
8. Has, at the initiation of study drug, received cytotoxic chemotherapy or a Bruton’s 
tyrosine kinase (BTK)-inhibitor (e.g. ibrutinib) within the past 3 weeks or rituximab 
within the past 2 months; for other anti-cancer therapies (approved or investigational) the 
interval will be determined in consultation with the Medical Monitor 
9. Has, at the initiation of study drug, an active infection requiring systemic antibiotics 
10. Has had within the 4 weeks prior to initiation of study drug, or is expected to have during 
the study period, surgery requiring general anesthesia  
11. Has active autoimmune cytopenia (anemia, thrombocytopenia, leukopenia) requiring 
concomitant therapy 
12. Has heart failure of Class III or IV (New York Heart Association criteria) 
13. Has sensory or motor neuropathy of Grade 4 (National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE v4.03 criteria]) 
14. Has other significant medical conditions (chronic or active within the past 6 months), 
including, but not limited to: cardiac disease (e.g., unstable angina, myocardial infarction, 
ventricular arrhythmia); uncontrolled seizure disorder; liver disease; or uncontrolled 
diabetes 
15. Has any other condition that would, in the opinion of the Investigator, potentially 
compromise the safety or compliance of the patient or may preclude the patient’s 
successful completion of the clinical trial 
16. History of another primary malignancy that has not been in remission for at least 3 years.  
The following are exempt from the 3 year limit: nonmelanoma skin cancer, curatively 
treated localized prostate cancer with nondetectable prostate specific antigen, and 
cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP smear 
17. Lactating or pregnant women 
1.6. 
Treatments 
1.6.1. 
Investigational Product, Dosage and Mode of Administration 
IMO-8400 administered as follows:  
• Dose levels of 0.6 to 3.6 mg/kg/week by body weight at Screening to be given as 
SC injections.  
• Injection volume will not exceed 1.2 mL/site, with multiple sites used per dose as 
necessary. 
• Dose to be recalculated if change in body weight from Screening exceeds 10% (±).  
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• Injections will be administered in the 4 quadrants of the abdomen or in the upper 
thighs, rotating injection site each time IMO-8400 is administered (see Section 8.4).  
• Scheduled duration of study treatment is until withdrawn consent, progressive 
disease, end of study, or intolerable toxicity with provision for dose adjustment in the 
event of a laboratory DLT or occurrence of a DME (see Section 6.5).  
1.6.2. 
Reference Therapy, Dosage and Mode of Administration 
Not applicable.  
1.7. 
Criteria for Evaluation 
1.7.1. 
Pharmacokinetics  
Pharmacokinetic samples will be obtained as scheduled in relation to first weekly dose 
administered on Day 1 of every cycle, at pre-dose and at 1 (± 5 minutes), 2 (± 10 minutes), and 
4 (± 15 minutes) hours post-dose.  A PK sample will also be taken at the EOT and EOS visits.  
Plasma samples will be analyzed for IMO-8400 concentration using a validated bioanalytical 
method.  Pharmacokinetic analysis will be conducted on an individual basis.  
For each cohort, the plasma IMO-8400 concentration data will be analyzed by 
non-compartmental PK analysis. The following parameters will be determined as appropriate: 
observed maximum plasma concentration (Cmax), time of Cmax (Tmax), and area under the curve 
from 0 to last measurable plasma concentration (AUC0-t).  Pharmacokinetic parameters will be 
compared across IMO-8400 dose levels. 
1.7.2. 
Safety 
Assessments for safety include: 
• Ongoing monitoring for clinical AEs.  
• Symptom review and vital signs at each scheduled visit.  
• Physical exam and electrocardiogram (ECG) (see Section 9.6). 
• Laboratory safety tests (hematology, serum complement, clinical chemistry, 
urinalysis) every 4 weeks (Section 9.7). 
• Injection site reactions (see Section 9.6.5) 
• Additional unscheduled assessments at Investigator’s discretion. 
Adverse events will be graded according to NCI CTCAE version 4.03.  Adverse events will be 
coded using Medical Dictionary for Regulatory Activities version 16.0 and tabulated by event, 
grade, and relationship to study therapy.  Laboratory results, vital signs, and ECG parameters 
will be summarized using descriptive statistics.  Laboratory values will also be graded according 
to NCI CTCAE, version 4.03, and summarized using shift tables.  
1.7.3. 
Treatment Effect 
Assessments of disease status will be conducted at Screening, every 4 weeks ± 1 week (Week 1 
and Week 5 of each cycle; for laboratory assessments, see Section 9.4.2), every 8 weeks 
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± 1 week (Week 1 of each cycle; for clinical assessments, see Section 9.4.1), every 12 weeks 
± 4 weeks during the Follow-up Phase, at the EOT visit, and at the EOS visit.  Disease 
assessments will be classified based on the guidelines of the VIth International Workshop [1].  
Time to progression and duration of response will be measured as defined. See Section 9.5 for 
details.  Patients discontinued from the study for reasons other than progressive disease will be 
assessed at a minimum of every 12 weeks ± 4 weeks until documentation of progressive disease, 
initiation of a subsequent anti-cancer therapy, or until the study ends, for up to 6 months from the 
first treatment (Cycle 1, Day 1) for the last patient enrolled, whichever comes first.  
1.8. 
Statistical Methods 
Safety observations will be analyzed using descriptive statistics and tabulation.  
Following identification of the MTD/RP2D, up to an additional 22 patients will be enrolled at the 
MTD or proposed RP2D level.  With a total sample size of 22 patients, there is a 90% probability 
to detect an AE with a true incidence rate of 10%.  A secondary objective of this study is to 
determine the treatment effect of IMO-8400 in patients enrolled at the MTD/RP2D.  Using the 
exact binomial distribution with a 1-sided test and an alpha of 0.05, there is 79% power to detect 
a response rate of 33% as compared to a null response rate of 10%. 
 
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1.9. 
Schedule of Assessments  
Table-4.  
Schedule of Study Events 
Visit1 
Scrn2 
Day 1 
Treatment Period 
EOT3 
EOS3 
F/U 
Cycle 
 
 
Cycle 1 
Even Numbered 
Cycles 
Odd Numbered 
Cycles 
 
 
Every 12 weeks 
(± 4 weeks) 
Week 
 
 
2-4 
5 
6-8 
1 
2-4 
5 
6-8 
1 
2-4 
5 
6-8 
 
 
 
Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients who discontinue 
for reasons other than 
progressive disease should 
be assessed per Response 
Assessment in WM24 until 
documentation of 
progressive disease, start of 
new anti-cancer therapy, 
until the study ends, or for 
up to 6 months from the 
last patient’s first treatment 
cycle, whichever one 
comes first. 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cryoglobulin & Cold Agglutinin Lab 
Tests6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination8  
X 
X 
X8 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Body weight7 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Height measurement 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs9,10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment for Tumor 
Status11 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Total IgM & Monoclonal Protein Lab 
Tests12 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
ECOG7 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
CT or MRI imaging13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Safety Laboratory Tests14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis7 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
12-lead ECG15 
X 
X15 
 
X15 
 
X15 
 
X15 
 
X15 
 
X15 
 
X 
 
Pregnancy test (females only)16 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK17 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Serum Cytokines18 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Antibodies to IMO-840018 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Serum NF-κB19 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Initial Dx Bone Marrow Slides20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Biopsy & Aspirate21 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Assessment of Injection Site22 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Administration10, 23 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AE & Concomitant Med Monitoring 
From Screening to EOS Visit 
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Abbreviations:  AE=adverse event; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOS=end-of-study; 
EOT=end-of-treatment; F/U=Follow-up; IgM=immunoglobulin M; NF-κB=nuclear factor kappa-light-chain-enhancer of activated B cells; 
PK=pharmacokinetic; MRI=magnetic resonance imaging; Scrn=Screening; WM=Waldenström’s macroglobulinemia 
1 Day 1 is the day of the first injection of study drug.  All weeks for a given cycle are relative to the day of the first injection of study drug for that Cycle and are 
defined as Day 1 through Day 7, inclusive; all times are relative to injection, designated 0 hour; “pre-dose” vital signs are to occur within 1 hour prior to 
injection; all other pre-dose procedures are to occur prior to injection on the same calendar day. 
2 Screening procedures may be performed up to 21 days prior to Day 1. 
3 If treatment is terminated prematurely for any reason, the EOT visit will be performed within 5 days of the decision to terminate; the EOS visit will be 
performed 30 to 35 days after the last dose of study drug. 
4 Informed consent must be signed prior to all study-specific screening procedures. 
5 Medical history includes, but is not limited to, a detailed review of the patient’s malignancy, prior treatments, relevant current or past abnormalities or diseases, 
and signs and symptoms of WM at baseline. 
6 Cryoglobulin and cold agglutinin laboratory testing to be performed at Screening (local laboratory). 
7 To occur pre-dose. 
8 During Cycle 1 only, physical examination will be done on Week 2.  In subsequent cycles, physical examinations will be done every 4 weeks. 
9 Vital signs comprise heart rate, blood pressure, respiratory rate and temperature. Vital signs will be obtained pre-dose (within 1 hour prior to injection) and 
post-dose at 30 (± 5) min after dosing. On Day 1 of Cycle 1, Week 1, post-dose vital signs will also be obtained at 2 hours (± 20 min). 
10 For patients who receive a second weekly dose, vital signs will be obtained pre-dose (within 1 hour prior to injection) and post-dose at 30 (± 5) min after 
dosing, and assessment of the injection site, as previously noted, will be conducted. 
11 Clinical assessment for tumor status will be conducted pre-dose on dosing visits and will include assessment for lymphadenopathy, hepatomegaly, and 
splenomegaly (see Section 9.4.1 for details).  
12 Assessments will be conducted pre-dose on dosing visits, and includes total serum IgM, monoclonal serum IgM, serum free light chains, urine free light 
chains, serum viscosity, and serum β2-microglobulin; see Section 9.4.2 for details. 
13 CT or MRI imaging of chest, abdomen, and pelvis with the same modality used for every assessment; see Section 9.4 for details. 
14 The full panel of safety laboratory tests (hematology, serum complement, chemistry and coagulation) will be done pre-dose on Day 1, and Weeks 1 and 5 of 
each cycle (including pre-treatment criteria presented in Section 8.4.1); a focused panel (hematology, selected chemistry) will be done pre-dose on Weeks 3 and 
7 of each cycle; see Section 9.7.1 for details. Unscheduled tests to confirm decreases in serum complement levels will be performed (see Section 6.5.4).  
15 ECGs are to be performed pre-dose and 2 hours post-dose on Day 1 of Cycle 1 and pre-dose at the first dosing visit of Weeks 1 and 5 of each cycle thereafter. 
In addition, an ECG is to be performed at 2 hours post-dose on Day 1 of each odd-numbered cycle. 
16 Serum pregnancy testing will be done pre-dose and evaluated at the central laboratory. 
17 PK samples will be collected as scheduled in relation to the first dose administered on Day 1 of every cycle.  Samples will be obtained pre-dose (within 1 hour 
prior to injection) and post-dose at 1 hour (± 5 min), 2 hours (± 10 min) and 4 hours (± 15 min) after dosing. PK samples will also be taken at EOT and EOS. 
18 Serum for cytokines and antibodies to IMO-8400 will be collected as scheduled in relation to the first dose administered on Day 1 of every cycle and will be 
obtained pre-dose (within 1 hour prior to injection).   
19 Serum samples for NF-κB analysis will be obtained pre-dose (within 1 hour prior to injection) and post-dose at 4 hours (± 15 min)  (see Section 9.9 for details) 
and will be submitted to central laboratory. 
20 Bone marrow slides will be obtained from initial WM diagnosis. 
21 Bone marrow biopsy and aspirate will be collected at Screening, EOT, and to document complete response as appropriate (see Section 16.2) and submitted to 
central laboratory (see Section 9.4.4 and Section 12.4.1).  If patients have a bone marrow biopsy within 4 weeks of EOT, the biopsy will not be repeated at 
EOT. The Screening Visit sample will also be assayed for the MyD88 L265P mutation. 
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22 Assessment of all prior injection site(s) with grading and measurement of any reaction (see Section 9.6.5).  In addition, on dosing days, the planned injection 
site will be assessed to confirm it is appropriate for use. 
23 Schedule applies to all patients receiving once weekly dosing and to the first weekly dose for all patients receiving twice weekly dosing (see Section 1.3.2 and 
Section 8.4 for details). 
24 Response assessment is summarized in Section 16.2 and includes total serum IgM, serum monoclonal IgM, bone marrow histology, adenopathy/organomegaly, 
cytopenias, and symptoms (see Section 9.5 for details). Total IgM and monoclonal protein lab tests (see Section 9.4.2 for details) will be submitted to central 
laboratory. 
 
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Table-5.  
Estimation of Blood Volumes Required From Screening through End-of-Study 
Tests 
Volume 
(mL) 
Screening 
(mL) 
Maximum Volume Per 
8-week Cycle (mL) 
EOT  
(mL) 
EOS 
(mL) 
Safety Lab Tests (full) 
19 
19 
38 
19 
19 
Safety Labs (focused) 
10 
 
20 
 
 
PK 
2 
 
8 
2 
2 
Serum Cytokines 
4 
4 
4 
4 
4 
Antibodies to IMO-8400 
4 
4 
4 
4 
4 
Serum NF-κB 
10 
 
20 
10 
10 
Tumor Assessments 
15 
15 
30 
15 
15 
Pregnancy test (F only) 
(extra blood volume is not 
required) 
X 
X 
X 
X 
X 
Serology 
10 
10 
 
 
 
Total mL blood drawn 
 
52 
124 
54 
54 
Abbreviations:  EOS=end-of-study; EOT=end-of-treatment; F=female; NF-κB=nuclear factor kappa-light-chain-
enhancer of activated B cells; PK=pharmacokinetic 
Note: The volumes shown are estimates; final volumes may vary, but will not be more than 15% greater than shown.  
 
 
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2. 
TABLE OF CONTENTS  
PROTOCOL 8400-401 ....................................................................................................................1 
1. 
SYNOPSIS ...................................................................................................................4 
1.1. 
Protocol Information .....................................................................................................4 
1.2. 
Objectives .....................................................................................................................4 
1.2.1. 
Primary Objective .........................................................................................................4 
1.2.2. 
Secondary Objectives ....................................................................................................4 
1.2.3. 
Exploratory Objectives .................................................................................................4 
1.3. 
Study Design and Methodology ...................................................................................5 
1.3.1. 
Brief Background and Rationale ..................................................................................5 
1.3.2. 
Study Overview .............................................................................................................5 
1.3.3. 
Dose-escalation Cohorts ..............................................................................................5 
1.3.4. 
Dose-escalation Procedures .........................................................................................6 
1.3.5. 
Dose-escalation Enrollment and Review ......................................................................6 
1.3.6. 
Expansion Cohorts........................................................................................................7 
1.3.7. 
Management of Study Treatment in Individual Patients ..............................................7 
1.4. 
Study Structure .............................................................................................................8 
1.5. 
Diagnosis and Patient Selection Criteria ......................................................................8 
1.5.1. 
Qualifying Disease ........................................................................................................8 
1.5.2. 
Inclusion Criteria ..........................................................................................................9 
1.5.3. 
Exclusion Criteria .........................................................................................................9 
1.6. 
Treatments ..................................................................................................................10 
1.6.1. 
Investigational Product, Dosage and Mode of Administration ..................................10 
1.6.2. 
Reference Therapy, Dosage and Mode of Administration ..........................................11 
1.7. 
Criteria for Evaluation ................................................................................................11 
1.7.1. 
Pharmacokinetics .......................................................................................................11 
1.7.2. 
Safety ...........................................................................................................................11 
1.7.3. 
Treatment Effect ..........................................................................................................11 
1.8. 
Statistical Methods ......................................................................................................12 
1.9. 
Schedule of Assessments ............................................................................................13 
2. 
TABLE OF CONTENTS ...........................................................................................17 
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3. 
LIST OF ABBREVIATIONS.....................................................................................25 
4. 
INTRODUCTION ......................................................................................................27 
4.1. 
Waldenström’s Macroglobulinemia (WM): the Disease under Study .......................27 
4.1.1. 
Current Standard of Care Therapy for WM ...............................................................27 
4.2. 
Role of Toll-like Receptors (TLRs) in B-cell Malignancy .........................................28 
4.3. 
Rationale for the Current Study ..................................................................................30 
4.4. 
Overview of IMO-8400 ..............................................................................................31 
4.4.1. 
Clinical Experience with WM .....................................................................................32 
4.4.2. 
Benefit/Risk Aspects ....................................................................................................32 
5. 
STUDY OBJECTIVES ..............................................................................................33 
5.1. 
Primary Objective .......................................................................................................33 
5.2. 
Secondary Objectives .................................................................................................33 
5.3. 
Exploratory Objectives ...............................................................................................33 
6. 
INVESTIGATIONAL PLAN .....................................................................................34 
6.1. 
Overall Study Design ..................................................................................................34 
6.2. 
Dose-escalation Cohorts .............................................................................................34 
6.3. 
Dose-escalation Procedures ........................................................................................35 
6.3.1. 
Definition of a Dose-Limiting Toxicity and Dose Modifying Event ...........................35 
6.3.2. 
Definition of Maximum Tolerated Dose and Recommended Phase 2 Dose ...............36 
6.3.3. 
Dose-escalation Enrollment and Review ....................................................................36 
6.4. 
Expansion Cohorts ......................................................................................................37 
6.5. 
Management of Individual Patients ............................................................................37 
6.5.1. 
Duration of Treatment ................................................................................................37 
6.5.2. 
Dose Modification in Patients with Laboratory DLT Events or DMEs .....................38 
6.5.3. 
Management of Systemic Injection Reactions ............................................................38 
6.5.4. 
Procedures for Assessment of Patients with Changes in Complement Levels ...........39 
6.5.5. 
Procedures for Assessment of Patients with Symptomatic Thrombocytopenia ..........39 
6.5.6. 
Classification of Patients at Termination of Treatment .............................................40 
6.6. 
Criteria for Replacement Patients ...............................................................................40 
6.6.1. 
Definition of a Evaluable Patient ...............................................................................40 
6.6.2. 
Replacement Patients ..................................................................................................40 
6.7. 
Maximum Number of Patients and Maximum Exposures .........................................41 
6.8. 
Treatment Assignment ................................................................................................41 
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6.9. 
Criteria for Study Termination ...................................................................................41 
6.10. 
Discussion of Study Design and Treatment Regimens ...............................................41 
6.10.1. 
Rationale for Study Structure .....................................................................................41 
6.10.2. 
Rationale for Treatment Regimens in Current Protocol ............................................42 
6.10.2.1. 
Dosing Regimen .........................................................................................................42 
6.10.2.2. 
Duration of Treatment ................................................................................................42 
7. 
SELECTION OF PATIENTS.....................................................................................43 
7.1. 
Source of Patients and Recruitment Methods .............................................................43 
7.2. 
Patient Restrictions during the Conduct of the Study .................................................43 
8. 
STUDY TREATMENT ..............................................................................................44 
8.1. 
Study Treatments to be Administered ........................................................................44 
8.2. 
Description and Manufacture of Study Drug ..............................................................44 
8.3. 
Reconstitution of IMO-8400 for Injection ..................................................................44 
8.4. 
Administration of Study Treatments ..........................................................................45 
8.4.1. 
Pre-Treatment Criteria ...............................................................................................45 
8.4.2. 
Variances in Dose Administration Schedule ..............................................................45 
8.5. 
Assigning Patients to Treatment Groups ....................................................................46 
8.6. 
Prior and Concomitant Medications ...........................................................................46 
8.6.1. 
Prohibited Treatments ................................................................................................46 
8.6.2. 
Other restrictions ........................................................................................................46 
8.7. 
Treatment Compliance ................................................................................................46 
8.8. 
Accountability of Investigational Drug Supplies .......................................................47 
8.8.1. 
Disposition of Study Drug ..........................................................................................47 
9. 
STUDY EVENTS AND EVALUATIONS ................................................................48 
9.1. 
Schedule of Events .....................................................................................................48 
9.2. 
Screening Procedure ...................................................................................................48 
9.3. 
Enrollment Procedure .................................................................................................49 
9.4. 
Assessments of Waldenström’s Macroglobulinemia ..................................................49 
9.4.1. 
Clinical Assessments ...................................................................................................49 
9.4.2. 
Laboratory Assessments Relating to Total IgM and Monoclonal Protein .................49 
9.4.3. 
Radiologic Imaging ....................................................................................................50 
9.4.4. 
Bone marrow biopsy and aspirate ..............................................................................50 
9.5. 
Evaluation of Response to Treatment and Disease Status ..........................................50 
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9.6. 
General Clinical Assessments .....................................................................................50 
9.6.1. 
Medical History, including WM .................................................................................50 
9.6.2. 
Physical Examination and Body Weight .....................................................................51 
9.6.3. 
Vital Signs ...................................................................................................................51 
9.6.4. 
Electrocardiogram ......................................................................................................51 
9.6.5. 
Injection Site Reaction (ISR) Assessments ..................................................................52 
9.7. 
Safety Laboratory Studies ...........................................................................................53 
9.7.1. 
Safety Laboratory Tests ..............................................................................................53 
9.7.2. 
Reporting of Safety Laboratory Tests .........................................................................54 
9.7.3. 
Repeating Abnormal Laboratory Tests .......................................................................54 
9.8. 
Pharmacokinetic Assessments ....................................................................................54 
9.9. 
Investigational Laboratory Studies .............................................................................54 
10. 
SAFETY ASSESSMENTS (ADVERSE EVENTS) ..................................................56 
10.1. 
Definition of Adverse Events .....................................................................................56 
10.1.1. 
Adverse Event .............................................................................................................56 
10.1.2. 
Serious Adverse Event ................................................................................................56 
10.1.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .......................................57 
10.2. 
Investigator Assessment of Safety Laboratory Tests ..................................................57 
10.3. 
Recording Adverse Events .........................................................................................58 
10.4. 
Characterizing Adverse Events ...................................................................................58 
10.4.1. 
Description of Event ...................................................................................................58 
10.4.2. 
Date and Time of Onset ..............................................................................................58 
10.4.3. 
Relationship to Study Drug .........................................................................................59 
10.4.4. 
Severity .......................................................................................................................59 
10.4.5. 
Grading of Laboratory Safety Tests for Reporting and Analysis ...............................60 
10.4.6. 
Management of Study Drug upon Occurrence of an Adverse Event ..........................60 
10.4.7. 
Actions Taken for Management of AE ........................................................................60 
10.4.8. 
Follow-up and Outcome of AEs ..................................................................................61 
10.4.9. 
Date and Time of Outcome .........................................................................................61 
10.5. 
Reporting Adverse Events ..........................................................................................62 
10.5.1. 
Where to Report SAEs ................................................................................................62 
10.5.2. 
Procedures for Reporting SAEs to the Sponsor ..........................................................62 
10.5.3. 
Other Reportable Events .............................................................................................63 
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10.5.4. 
Requirements for Expedited and Periodic Reporting of Adverse Events ...................63 
10.5.5. 
Notification of SAEs to the Investigator by the Sponsor .............................................63 
11. 
DATA QUALITY ASSURANCE ..............................................................................64 
11.1. 
Compliance .................................................................................................................64 
11.2. 
Training and Qualifications of Site Personnel ............................................................64 
11.3. 
Source Documents ......................................................................................................64 
11.3.1. 
Study-Specific Source Documents ..............................................................................65 
11.4. 
Electronic Case Report Forms ....................................................................................65 
11.5. 
Protocol Deviations ....................................................................................................66 
11.6. 
External Review of the Study Conduct at Participating Sites ....................................66 
11.7. 
Study Monitoring Visits .............................................................................................67 
11.7.1. 
Site Qualification and Initiation Visits .......................................................................67 
11.7.2. 
Interim Monitoring Visits ...........................................................................................67 
11.7.3. 
Study Closeout Visit ....................................................................................................68 
11.8. 
Resolution of Deficiencies ..........................................................................................68 
11.9. 
Retention of Records ..................................................................................................68 
11.10. 
Data Management .......................................................................................................69 
12. 
STATISTICS ..............................................................................................................70 
12.1. 
Sample Size Determination and Study Power ............................................................70 
12.2. 
Analysis Populations ..................................................................................................70 
12.3. 
Analysis of Safety .......................................................................................................70 
12.4. 
Analysis of Treatment Effect ......................................................................................71 
12.4.1. 
Assessments .................................................................................................................71 
12.4.1.1. 
Primary Treatment Effect Parameter ..........................................................................71 
12.4.1.2. 
Secondary Treatment Effect Parameters ....................................................................71 
12.5. 
Exploratory Analyses ..................................................................................................72 
12.6. 
Identification of Study Event Days and Times ...........................................................72 
12.7. 
Handling Missing Data ...............................................................................................72 
12.8. 
Changes in the Planned Analyses ...............................................................................72 
13. 
ETHICAL CONSIDERATIONS................................................................................73 
13.1. 
Independent Ethics Committee (IEC) .........................................................................73 
13.1.1. 
Initial Review Prior to Study Initiation ......................................................................73 
13.1.2. 
Subsequent Submissions to the IEC ............................................................................74 
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13.2. 
Written Informed Consent ..........................................................................................74 
13.2.1. 
Obtaining Informed Consent from Patients Who Are Not Literate ............................75 
13.2.2. 
Special Informed Consent Situations Not Applicable to This Protocol ......................75 
13.2.3. 
Protection of Patient Information ...............................................................................75 
14. 
STUDY ADMINISTRATION ...................................................................................76 
14.1. 
Registration of Study ..................................................................................................76 
14.2. 
Changes in the Conduct of the Study .........................................................................76 
14.3. 
Confidentiality ............................................................................................................76 
14.4. 
Financial Disclosure ...................................................................................................76 
14.5. 
Publication Policy .......................................................................................................77 
14.6. 
Authorship and Acknowledgement ............................................................................77 
15. 
LIST OF REFERENCES ............................................................................................78 
16. 
CRITERIA FROM THE INTERNATIONAL WORKSHOPS ..................................80 
16.1. 
Diagnostic Criteria for Waldenström’s Macroglobulinemia ......................................80 
16.2. 
Classification of Disease Response for Waldenström’s Macroglobulinemia .............81 
16.3. 
Efficacy Measure Definitions .....................................................................................82 
17. 
INVESTIGATOR’S AGREEMENT ..........................................................................83 
 
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List of Tables 
Table-1.  
Emergency and Pharmacovigilance Contacts ...............................................................3 
Table-2.  
Study Contact Information ...........................................................................................3 
Table-3. 
Planned Dose Escalation Cohorts .................................................................................6 
Table-4.  
Schedule of Study Events ...........................................................................................13 
Table-5.  
Estimation of Blood Volumes Required From Screening through End-of-
Study ...........................................................................................................................16 
Table-6.  
Incidence of MyD88 L265P mutation in selected B-cell malignancies .....................30 
Table-7.  
Clinical Studies with IMO-8400 in Addition to This Study .......................................32 
Table-8. 
Planned Dose Escalation Cohorts ...............................................................................34 
Table-9.  
Physical and Chemical Properties of Active Ingredient (Drug Substance) ................44 
Table-10.  Formulation of IMO-8400 for Injection (Drug Product) ............................................44 
Table-11. IMO-8400 Subcutaneous Injection Site Grading (Local Reactions) ..........................52 
Table-12. Intensity of AE of Injection Site Reactiona ................................................................53 
Table-13.  Reporting the Date and Time of Onset of adverse events for Different Types 
of Events .....................................................................................................................58 
Table-14.  Estimating Severity Grade ..........................................................................................60 
Table-15.  Date and Time of Outcome for Adverse Event by Outcome Class ............................61 
 
 
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List of Figures 
Figure-1.  TLR and BCR Signaling Pathways in B-cells ............................................................29 
 
 
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3. 
LIST OF ABBREVIATIONS 
Abbreviation  Explanation 
ABC-DLBCL 
Activated B-cell (type) Diffuse Large B-cell Lymphoma 
AE 
Adverse event 
ALT 
Alanine amino-transferase 
AP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate amino-transferase 
β-hCG 
Beta-human chorionic gonadotropin 
BA 
Bioavailability 
BCR 
B-cell receptor 
BE 
Bioequivalence 
BP 
Blood pressure 
BTK 
Bruton’s tyrosine kinase 
C3 
Complement component 3 
C4 
Complement component 4 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CH50 
50% hemolytic complement assay 
CK 
Creatine phosphokinase 
CNS 
Central nervous system 
CR 
Complete response 
CRP 
C-reactive protein 
CS 
Clinically significant 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose-limiting toxicity 
DME 
Dose modifying event 
DNA 
Deoxyribonucleic acid 
DRC 
Data Review Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EE 
Efficacy Evaluable 
EHR 
Electronic Health Record 
EOS 
End-of-study 
EOT 
End-of-treatment 
FDA 
Food and Drug Administration (US) 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High density lipoprotein 
HIV 
Human immunodeficiency virus 
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HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent ethics committee 
IFN 
Interferon 
IgM 
Immunoglobulin M 
IL 
Interleukin 
IND 
Investigational new drug 
INN 
International nonproprietary name 
INR 
International normalized ratio 
IP-10 
Interferon-inducible protein-10 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
ITT 
Intent-to-treat 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MTD 
Maximum tolerated dose 
MyD88  
Myeloid differentiation primary response gene (88) 
MR 
Minor response 
MRI 
Magnetic resonance imaging 
NA 
Not applicable 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NF-κB 
Nuclear factor kappa-light-chain-enhancer of activated B cells 
NCS 
Not clinically significant 
PP 
Per-protocol 
PR 
Partial response 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin Time 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TLR 
Toll-like receptor 
TMF 
Trial master file  
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
VGPR 
Very good partial response 
WBC 
White blood cell 
WM 
Waldenström’s macroglobulinemia 
WMA 
World Medical Association 
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4. 
INTRODUCTION 
4.1. 
Waldenström’s Macroglobulinemia (WM): the Disease under Study  
Hematological malignancies are cancers affecting blood, bone marrow, and lymph nodes; they 
may derive from either myeloid or lymphoid cell lines.  Malignancies arising from the myeloid 
line include acute and chronic myelogenous leukemia, myelodysplastic syndromes, and 
myeloproliferative diseases.  Those arising from the lymphoid line include lymphoma, 
lymphocytic leukemia, multiple myeloma, and WM.  Chromosomal abnormalities – both point 
mutations and translocations – are common among hematological malignancies, have an 
established role in diagnosis, and are increasingly used in guiding specific approaches to 
treatment. 
Waldenström’s macroglobulinemia is a distinct B-cell lymphoproliferative disorder characterized 
by a lymphoplasmacytic infiltrate in the bone marrow and high levels of a monoclonal 
immunoglobulin M (IgM) in the serum [6,7].  The disease can have a chronic, indolent course, 
with patients remaining asymptomatic for years.  The principal complications include:  
− Manifestations of the monoclonal gammopathy, including symptomatic 
hyperviscosity, cryoglobulinemia, and cold agglutinin disease. 
− Disease-related cytopenia. 
− Bulky adenopathy or organomegaly. 
− Severe neuropathy. 
− Amyloidosis. 
− Disease transformation. 
4.1.1. 
Current Standard of Care Therapy for WM 
Current recommendations are that asymptomatic patients with WM are observed and that 
treatment should not be based on IgM levels alone.  Treatment should be initiated in response to 
the clinical complications noted above [6,8].  Selection of therapeutic agents may be tailored to 
the disease manifestations.  The most common first-line regimens are combinations including the 
following agents: 
− Rituximab (anti-CD20 monoclonal antibody). 
− Cyclophosphamide or chlorambucil (alkylating agents). 
− Doxorubicin (anthracycline antibiotic). 
− Vincristine (alkaloid). 
− Prednisone (corticosteroid). 
− Fludarabine or cladribine (nucleoside analogs). 
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Ibrutinib has recently received Food and Drug Administration approval for the treatment of WM 
on the basis of a response rate of 61.9% (including complete response [CR], very good partial 
response [VGPR], and partial response [PR]) in a Phase 2 study of 63 patients.  
Plasmapheresis is used for symptomatic hyperviscosity and other complications of high serum 
levels of monoclonal IgM protein.  
Salvage therapy for patients with refractory or relapsing disease is diverse and use of 
investigational agents is often considered appropriate.  Approaches in current practice include 
(a) alternative combinations of the agents noted above, with the possible addition of bortezomib 
or thalidomide, and (b) transplantation with autologous stem cells or allogenic bone marrow 
[6,7].  
Many of the agents used in refractory or relapsing WM are cytotoxic or sharply 
immunosuppressive and have substantial safety risks in elderly patients characteristic of this 
disease.  A novel targeted agent that provided a beneficial treatment effect with a better 
tolerability profile would address an unmet need in WM.  
4.2. 
Role of Toll-like Receptors (TLRs) in B-cell Malignancy 
Toll-like receptors are a family of host sensors for “foreign” constituents (e.g., nucleic acids, 
lipopolysaccharides, peptidoglycans from viruses, bacteria, fungi) that “sound the alarm” and 
activate host immune defenses.  The natural ligands for TLR7 and 8 are single-stranded 
ribonucleic acid (RNA) from viruses, and for TLR9, unmethylated cytosine-guanine dinucleotide 
motifs (CpG), which are characteristic of bacterial deoxyribonucleic acid (DNA).  Binding of 
these ligands to the cognate receptor results in intracellular signaling, generation of nuclear 
factor kappa-light-chain-enhancer of activated B cells (NF-κB), and production of 
pro-inflammatory (Th1) chemokines and cytokines, including interferon (IFN)-α, tumor necrosis 
factor (TNF)-α and interleukin (IL)-12.  Of note, TLRs 7, 8, and 9 are located in the endosome, 
whereas most other TLRs, which are located on the host cell surface. In man, the endosomal 
TLRs are expressed primarily on dendritic cells and B-cells. 
Although foreign constituents are the intended ligands for the nucleic acid TLRs, multiple 
studies indicate that activation by endogenous nucleic acids is central to the development and 
persistence of autoimmunity and inflammatory diseases. [9,10,11,12,13].  
The TLR signaling pathway (Figure-1, left panel) comprises a series of cytoplasmic proteins that 
result in generation of NF-κB, which translocates to the nucleus and mediates increased 
expression of genes involved in cell survival, proliferation, and cytokine production.  In B-cells, 
the other major mechanism for activation is binding of specific antigen to the B-cell receptor 
(BCR).  There are several signaling pathways associated with the BCR (Figure-1, right panel), 
including one that generates increased NF-κB.  The constituents of that BCR signaling pathway 
are, in general, distinct from those of the TLR pathway.  
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Figure-1.  TLR and BCR Signaling Pathways in B-cells 
 TLR signaling 
BCR signaling [3] 
 
Abbreviations:  BCR=B-cell receptor; TLR=Toll-like receptor 
A central feature of malignant cell transformation is the development of dysregulated or 
autonomous cell activation resulting in increased cell proliferation and survival. This can be the 
result of specific ‘oncogene’ mutations or defects in the control of the expression of critical 
genes.  Studies of B-cell malignancies have identified changes in the BCR signaling pathway, 
and more recently in the TLR signaling pathway, that drive NF-κB expression and the malignant 
phenotype.  These changes include:  
• Mutations in BCR pathway genes, including CD79A/B and CARD11 [3]. 
• Increased expression of myeloid differentiation primary response gene (88) (MyD88), 
the adapter (linker) protein that binds to TLRs [14]. 
• Mutations in MyD88 [15]. 
The most common alternation identified to date in MyD88 is the L265P mutation.  Table-6 
displays the frequency of MyD88 L265P among B-cell malignancies and proliferative diseases.  
The mutation is present in over 90% of WM, in ~30% of Activated B-cell-like Diffuse Large 
B-cell Lymphoma, and at lower frequencies in other, more common lymphomas.  
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Table-6.  
Incidence of MyD88 L265P mutation in selected B-cell malignancies 
Disease 
Incidence of 
Disease 
(SEER 2001) 
% Patients with 
MYD88 L265P 
mutation 
Estimated  
Incidence 2013a  
(New cases/year) 
Reference for 
MyD88 
frequency 
ABC-DLBCL 
6,789b 
29% 
2,150 
[16] 
Waldenström’s 
macroglobulinemia 
1,144 
91% 
1,200 
[2] 
Chronic Lymphocytic Leukemia 
16,984 
3%, 7% 
925 
[17,18] 
Primary CNS Lymphoma 
1,200 
36%, 38% 
480 
[19,20] 
Marginal Zone Lymphomac  
3,247 
9%, 4% 
225 
[16,21] 
Abbreviations:  ABC-DLBCL=Activated B-cell (type) Diffuse Large B-cell Lymphoma; CNS=central nervous 
system; DLBCL=Diffuse Large B-cell Lymphoma; MyD88=Myeloid differentiation primary response gene (88); 
SEER=Surveillance Epidemiology and End Results 
a. New cases/year are adjusted + 10% due to population growth since data collection [22,23] 
b. Incidence of DLBCL, 24,246; ABC-type represents 28% of all DLBCL.  
c. Marginal Zone Lymphoma is also referred to as MALT, Mucosa-Associated Lymphoid Tissue Lymphoma 
Recent in vitro studies of B-cell tumor lines with L265P mutation suggest that increased TLR 
signaling contributes to the malignant phenotype of these cells [4].  Specifically, cell 
proliferation and survival decreased markedly under the following conditions: 
• Impaired expression of endosomal TLRs, using an inhibitory RNA. 
• Enzymatic elimination of endogenous nucleic acids in the culture supernatant. 
Idera Pharmaceuticals, Inc. has conducted independent studies using B-cell tumor lines, 
including LY10, a cell line with the L265P mutation and increased MyD88 expression.  LY10 
cells cultured in vitro with IMO-8400 demonstrated decreased growth and survival (see 
Investigator Brochure for details).  Severe combined immunodeficient mice inoculated with 
LY10 developed progressive disease and died.  Treatment with IMO-8400 prolonged median 
survival from 33 to 48 days (see Investigator’s Brochure for details).  
Taken together, these data directly support the hypothesis that an antagonist of TLR7, 8, and 9 
would have a therapeutic effect in patients with B-cell malignancies, particularly those 
characterized by MyD88 L265P mutation or increased MyD88 expression.  
4.3. 
Rationale for the Current Study 
IMO-8400 is a synthetic oligonucleotide that blocks activation mediated through TLR7, 8 and 9; 
that is, it functions as an antagonist for those receptors.  
To date, IMO-8400 in doses up to 0.6 mg/kg once weekly has been administered for 4 weeks in 
healthy volunteers and for 12 weeks in a completed Phase 2 psoriasis study (see Section 4.4 for 
details).  All treatments were well-tolerated, with mild injection site reactions and no pattern of 
systemic reactions or laboratory changes. 
As detailed above, recent studies indicate a role for TLR activation and subsequent signal 
amplification by MyD88 L265P mutation in the activation, proliferation, and increased survival 
of malignant B-cells.  
The current protocol represents the first use of IMO-8400 in patients with a B-cell malignancy.  
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4.4. 
Overview of IMO-8400 
IMO-8400 has been created by Idera Pharmaceuticals, Inc. using a structure-activity approach to 
design TLR-targeted drug candidates.  IMO-8400 is a synthetic oligonucleotide designed to 
inhibit immune responses mediated through endosomal TLR7, TLR8, and TLR9.  
Non-clinical studies (reviewed in detail in the Investigator’s Brochure) have demonstrated that 
IMO-8400 is an immunomodulatory agent with the following characteristics:  
• Acts as an antagonist for activation of TLR7, 8 and 9, specifically blocking the 
activity of agonists for those receptors, including inhibiting generation of NF-κB and 
induction of cytokines and chemokines (e.g., TNF-α, IL-12, IL-1β, IFN-inducible 
protein-10 [IP-10], IL-6, IFN-α). 
• Has no agonist activity; that is, does not induce Th1 cytokines/chemokines.  
• Is specific for endosomal TLRs 7, 8, and 9; that is, has no effect on activation of other 
unrelated TLRs, such as TLR4, whose natural ligand is bacterial lipopolysaccharide.  
• Has potent therapeutic activity in animal models of autoimmune diseases to inhibit 
the progression or reverse the clinical and immunologic manifestations of disease. 
Further, Idera has recently completed laboratory studies both in vitro and in mice examining the 
effect of IMO-8400 on human lymphoma B-cell lines, including cell lines with and without 
mutations in the TLR signaling pathway.  These studies demonstrate that IMO-8400 has the 
following effects: 
• Inhibits constitutively active cell signaling pathways, including NF-κB, IRAK, 
STAT-3, Jak/Stat, and BTK, in human lymphoma cell lines with the MYD88 L265P 
mutation.  
• Decreases in vitro cell survival and proliferation in a time- and 
concentration-dependent manner in human lymphoma cell lines with the MYD88 
L265P mutation.  
• Decreases tumor cell growth in vivo, as indicated by decreased serum levels of 
tumor-secreted cytokine, and increased mouse survival time in a disseminated 
xenograft model using OCI-Ly10, a human lymphoma cell line with the MYD88 
L265P mutation. 
• Decreases tumor growth and serum levels of tumor-secreted IL-10 in a subcutaneous 
(SC) xenograft mouse model using OCI-Ly10, a human lymphoma cell line with the 
MYD88 L265P mutation.  
• Does not impact tumor growth and tumor-secreted cytokines in a SC xenograft mouse 
model using SU-DHL-6, a human lymphoma cell line with wild-type MYD88.  
Clinical studies with IMO-8400 are summarized in Table-7 and the IB.  Clinical experience with 
IMO-8400 related to the rationale for the dosing regimen in the current study is provided in 
Section 6.10.2. 
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Table-7.  
Clinical Studies with IMO-8400 in Addition to This Study 
Protocol No.  
Protocol Title 
Status 
8400-001 
A Phase 1, Single-Dose Escalation and 4-week Multiple-Dose Escalation Study 
of the Safety and Pharmacokinetics of IMO-8400 in Healthy Volunteers 
Completed 
8400-201 
A Randomized, Double-Blind, Placebo-Controlled, 12-week Dose-Ranging Trial 
of IMO-8400 in Patients with Moderate to Severe Plaque Psoriasis 
Completed 
8400-402 
Phase 1/2 Open-label, Multiple-dose, Dose-escalation Study to Evaluate the 
Safety and Tolerability of IMO-8400 in Patients with Relapsed or Refractory 
Diffuse Large B-cell Lymphoma and Presence of the MyD88 L265P Mutation 
Ongoing 
8400-404 
An Extension Study to Evaluate the Long-Term Safety, Tolerability, and Clinical 
Activity of IMO-8400 in Patients with Relapsed or Refractory Waldenström’s 
Macroglobulinemia who Completed Study 8400-401 
Ongoing 
8400-211 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial of IMO-8400 in 
Patients with Dermatomyositis 
Ongoing 
Abbreviations: MyD88=Myeloid differentiation primary response gene (88) 
4.4.1. 
Clinical Experience with WM 
As of August 2015, 19 patients have been treated in this Phase 1 study with IMO-8400 at doses 
of 0.6, 1.2, and 2.4 mg/kg/week.  IMO-8400 was generally well tolerated at all dose levels.  Most 
reported adverse events (AEs) deemed related or possibly related to study drug were mild or 
moderate (National Cancer Institute Common Terminology Criteria for Adverse Events 
[NCI CTCAE] grade 1 or 2).  The most common AEs observed were fatigue, injection site 
erythema, headache, injection site pain, nausea, and pain in extremity.  Reported injection site 
reactions included grade 1 erythema, grade 1 pain, and grade 1 induration.  No injection site 
blistering, necrosis, pruritus, ulceration, or tenderness were reported.  Grade 3 AEs reported as 
possibly or probably related to study drug included neutropenia, anemia, and arthritis.  One of 
88 patients treated at the 2.4 mg/kg dose level experienced a dose-limiting toxicity (DLT) that 
was deemed possibly related to study drug; this patient experienced a grade 3 probable flare of 
pre-existing arthritis.  No deaths or grade 4 events were reported.  
Early signals of efficacy include 3 responses among 11 patients treated at the 0.6 and 1.2 mg/kg 
dose levels.  Among 6 evaluable patients treated at the highest dose level (2.4 m/kg), 3 had 
responses and 2 had stable disease [24].   
4.4.2. 
Benefit/Risk Aspects 
The starting dose level for the present study (0.6 mg/kg once weekly by SC injection) has been 
well tolerated for up to 4 weeks in healthy volunteers and up to 12 weeks in patients with 
moderate to severe psoriasis.  The majority of treatment-emergent adverse events (TEAEs) are 
mild injection site reactions; there were no treatment-related serious adverse events (SAEs) or 
discontinuations due to AEs.  This starting dose is, therefore, considered to represent minimal 
risk.  
In the context that patients enrolled in this study have no therapeutic options likely to extend 
their survival, the clinical and safety profile demonstrated thus far with IMO-8400 justifies their 
inclusion and their treatment until progression. 
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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective 
• To evaluate the safety and tolerability of escalating dose levels of IMO-8400 
administered by SC injection in patients with relapsed or refractory WM.  
5.2. 
Secondary Objectives 
• To assess the treatment effect (clinical activity) of escalating dose levels of 
IMO-8400 using disease-specific international guidelines for classifying clinical 
response [1].  
• To identify an optimal dose of IMO-8400 for further clinical evaluation. 
• To characterize the pharmacokinetics (PK) of escalating dose levels of IMO-8400 
administered by SC injection.  
5.3. 
Exploratory Objectives 
• To investigate associations between the treatment effect of IMO-8400 and selected 
biomarkers (e.g., serum cytokines). 
• To correlate the presence of MyD88 L265P mutation with clinical outcome. 
• To assess the potential immunogenicity of IMO-8400 administered by SC injection. 
 
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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is an open-label, multiple-dose, dose escalation study of IMO-8400 in patients with relapsed 
or refractory WM. 
6.2. 
Dose-escalation Cohorts 
The dose escalation cohorts (3 to 6 patients each) will systematically evaluate the safety and 
tolerability of IMO-8400 at increasing dose levels in order to identify the MTD/recommended 
Phase 2 dose (RP2D).  
• The planned dose escalation cohort levels for IMO-8400 are 0.6, 1.2, 2.4, and 
3.6 mg/kg administered once weekly and 1.2 mg/kg administered twice weekly 
(Table-8). Additional dose levels, schedules, and routes of administration may be 
evaluated based upon the emerging data. Weekly exposure is based on body weight 
(see Section 8.1 for details). Doses will be administered by SC injection.  
• For Dose Level 3 (refer to Table-8), the total dose will be divided into 2 equal 
portions (1.2 mg/kg twice weekly), administered as separate SC injections over the 
course of the week, preferably 72 to 96 hours apart (minimum 48 hours) (see 
Section 8.4 for details).  
• Once safety has been established for the 2.4 mg/kg/week as a divided weekly dose 
(1.2 mg/kg twice weekly), the same dose level of 2.4 mg/kg/week and subsequent 
dose levels will be given as a once weekly administration. 
• Once the RP2D/MTD has been established, patients being treated at lower dose levels 
may have their doses escalated to the RP2D/MTD upon discussion and agreement 
between the Sponsor and the Investigator.  
Table-8. 
Planned Dose Escalation Cohorts 
Dose Level 
IMO-8400 Dose (mg/kg)  
Frequency 
Initial Cohort Size 
1 (starting dose) 
0.6 
Once Weekly 
3-6 
2 
1.2  
Once Weekly 
3-6 
3 
1.2 
Twice Weekly 
3-6 
4 
2.4 
Once Weekly 
3-6 
5 
3.6 
Once Weekly 
3-6 
 
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6.3. 
Dose-escalation Procedures 
6.3.1. 
Definition of a Dose-Limiting Toxicity and Dose Modifying Event 
The safety and tolerability of IMO-8400 will be assessed using reported and observed AEs as 
well as scheduled safety observations including vital signs, physical examination, laboratory 
tests (hematology, chemistry, and coagulation), urinalysis, and electrocardiograms (ECGs).  
A DLT can be either a clinical or laboratory AE. 
A potential DLT event is defined as a treatment-emergent AE (see Section 10.1) which occurs 
within the first 5 weeks of treatment and meets any of the following criteria using NCI CTCAE 
grading (see Section 10.4.4):  
• Is a clinical event of Grade 3 or higher severity, except for the following: 
− Alopecia 
− Grade 3 fatigue 
− Grade 3 nausea/vomiting that has not been treated with optimal anti-emetic 
treatments 
− Grade 3 diarrhea that has not been treated with optimal anti-diarrheal treatments 
− AE related to the underlying disease 
• Is a confirmed laboratory finding of Grade 3 or higher severity (see Section 10.4.5) 
and has been assessed as related to IMO-8400 (any relationship other than “not 
related”) with the exceptions of neutropenia and thrombocytopenia.  DLTs with 
respect to neutropenia/thrombocytopenia are outlined below: 
− Grade 4 neutropenia lasting > 7 days  
− Grade 3 or 4 neutropenia with a sustained temperature > 101.3o F 
− Grade 3 thrombocytopenia associated with clinically significant bleeding that 
requires transfusion therapy 
− Grade 4 thrombocytopenia  
Clinically significant toxicities or TEAEs that meet the definition of dose-limiting but occurring 
after Week 5 of Cycle 1 are defined as dose modifying events (DMEs) and may be considered 
when determining the RP2D.   
The Data Review Committee (DRC) is comprised of the Idera Medical Monitor and 
Investigators from participating sites. The DRC will review all potential DLT events to assess 
causality, i.e., relationship to study drug (see Section 10.4.3).  Events will be considered DLT 
events unless they are unanimously assessed as “Not related,” that is, a factor other than study 
drug is the cause of the event (see Section 10.4.3).   
The definition of a DLT event will be applicable in the following contexts: 
• DRC review determining dose escalation (see below). 
• DRC review in defining the MTD (see below) or RP2D. 
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• Investigator (and Medical Monitor) review for determining pausing or 
discontinuation of study treatment in individual patients (see Section 6.5). 
6.3.2. 
Definition of Maximum Tolerated Dose and Recommended Phase 2 Dose 
The MTD is the highest dose level meeting both of the following criteria:  
• It is below the level at which 2 or more patients experienced DLTs during the first 
4 weeks of treatment;  
• It is a dose level at which no more than 1 patient experienced DLTs during the first 
4 weeks of treatment. 
The RP2D will be a dose at or below the MTD based on clinical data. 
6.3.3. 
Dose-escalation Enrollment and Review 
Each dose-escalation cohort is expected to enroll at least 3 patients, with a maximum of 6.  
• If the initial 3 patients all complete 4 weeks of treatment without a DLT event, the 
DRC will conduct a dose-escalation review.  
• If 1 of the initial 3 patients experiences a DLT event prior to completing 4 weeks of 
treatment, then enrollment at that dose level will continue to a total of 6 patients and 
the dose-escalation review will be done when all 6 patients have completed 4 weeks 
treatment. 
• If 2 patients at a dose level experience DLT events during the first 4 weeks of 
treatment, then no further patients will be enrolled until the DRC completes a review, 
which should be done as soon as feasible.  
Once the last patient in a given cohort has a completed 4 weeks of study treatment, a 
DRC meeting will be convened to review all safety data and to decide whether to continue or 
halt dose escalation, or explore intermediate dose levels.  To facilitate standardizing the 
dose-escalation reviews across different cohorts, the focus will be on observations from the first 
4 weeks of treatment at that dose level.  
The following represent anticipated outcomes for the review process (refer to DRC Charter for 
full details):  
• Dose escalation – progression to the next planned dose level.  
• Continue cohort enrollment (applicable only to review after 3 patients) – enroll up to 
6 patients at the current dose level to obtain additional safety data for subsequent 
review. 
• Dose de-escalation – enrollment of intermediate dose levels for exploration of other 
schedules of administration (see Section 6.5.2).  
• Approve enrollment in an expansion cohort at a selected dose level, if applicable (see 
Section 6.4). 
• No further dose escalation enrollment – at this time the DRC will indicate the dose 
level that they consider represents the MTD.  
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6.4. 
Expansion Cohorts 
The expansion cohorts provide for additional enrollment at agreed upon dose levels to assess the 
dose dependence of clinical response.   
Once the MTD or a potential RP2D and/or schedule have been established during dose 
escalation, up to 22 patients will be treated at the RP2D level according to this schedule.  The 
Sponsor may decide at any point during the expansion phase to modify the RP2D based on 
emerging data including, but not limited to, safety, DLTs, PK, and clinical activity.  If such a 
change is made, enrollment may continue at the selected dose level in up to 22 patients.  
6.5. 
Management of Individual Patients 
6.5.1. 
Duration of Treatment  
Each enrolled patient will receive IMO-8400 at the assigned dose level until the earliest of: 
• Clinical DLT event – see Section 6.3.  
− Study treatment will be discontinued in patients determined to have a clinical 
DLT event until resolution and may only be resumed after discussion with an 
Idera Medical Monitor and agreement that it is in the patient’s best interest to 
continue. 
− For a DME, provision is made for interrupting dosing for up to 3 weeks and, if the 
acute toxicity improves sufficiently, resuming treatment at a lower dose level 
based on discussion between the sponsor’s designated medical monitor and the 
treating physician. 
− For DLT laboratory events, provision is made for pausing treatment for up to 
3 weeks and, if the acute toxicity improves sufficiently, resuming treatment at a 
lower dose level (see Section 6.5.2 for details).  
− The Investigator will review with the Medical Monitor decisions to discontinue, 
pause, and/or restart study treatment. 
• Disease progression – based on scheduled assessments at Week 1 of each cycle.  
Unscheduled assessments may be conducted in response to new clinical observations.  
Disease status will be classified according to international guidelines [1] (see 
Section 9.5 for details).  
• Termination of participation in the study – due to AE, withdrawal of consent, 
intolerable toxicity, or loss to follow up.  
In certain instances, patients may be deriving clinical benefit despite objective signs of 
progressive disease such as radiologic progression.  It can be anticipated that based on the study 
drug’s mechanism of action, through an immunologic mediated effect, signs of radiologic 
response may be delayed.  Based on these considerations, continuing to treat some patients past 
progressive disease may be considered after discussion between the Sponsor and Investigator, 
provided the following conditions are met: 
• Patient has not achieved an objective response on study and then developed 
progressive disease; 
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• Patient has not experienced a period of clinically significant stable disease on study 
and then developed progressive disease; 
• Patient must be re-evaluated 4 to 6 weeks after initial progression in order to confirm 
progressive WM disease; 
• If the follow-up assessment does not confirm progressive disease, patient may resume 
regularly scheduled follow-up per protocol; 
• Patient must not have symptoms/signs indicative of clinically significant disease 
progression; 
• Patient must not have a decline in Eastern Cooperative Oncology Group (ECOG) 
performance status; 
• Patient must not have rapidly progressive disease or tumor progression at critical 
anatomic sites (e.g., cord compression) requiring urgent medical intervention. 
6.5.2. 
Dose Modification in Patients with Laboratory DLT Events or DMEs  
Patients determined to have a laboratory DLT event or DME (Section 6.3.1) may resume 
treatment after dose interruption and with dose modification if all of the following criteria are 
met.  
• The patient is receiving > 0.6 mg/kg/week; patients receiving 0.6 mg/kg/week will be 
discontinued.  
• The patient has not previously had dose interruption and/or adjustment for a 
laboratory DLT event or DME. 
• Both the Investigator and the Medical Monitor consider that continued treatment with 
study drug is in the patient’s interest.  
• The abnormal laboratory parameter(s) representing the DLT event or DME improve 
at least 2 grades or back to baseline within 14 days of the last dose administered.  
If, for any reason, dosing is interrupted more than 21 calendar days due to toxicity, the patient 
should be discontinued from study treatment unless the Investigator and the Idera Medical 
Monitor agree that it is in the patient’s best interest to continue. 
If dose modification is required, patients should resume dosing at the next lowest dosing level 
(see Table-8).    
6.5.3. 
Management of Systemic Injection Reactions 
Fever, chills, and rigors have been reported in the first 24 hours following IMO-8400 injection. 
These symptoms have responded well to symptomatic measures without long-term 
consequences.  Prophylaxis with acetaminophen and diphenhydramine may be considered for 
patients who experience these symptoms with prior injections.  Treatment should be 
discontinued for patients who experience more significant reactions (e.g., anaphylaxis or 
cardiovascular collapse) and full supportive care provided, as per institutional practice.    
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6.5.4. 
Procedures for Assessment of Patients with Changes in Complement Levels 
Activation of complement in non-human primates is a well-described effect of phosphorothioate 
oligonucleotides, including IMO-8400.  Monkeys are thought to be particularly sensitive to 
oligonucleotide-induced complement activation and a similar direct oligonucleotide-induced 
complement activation has not been observed in humans or other species.  Specifically, in a 
39 week chronic toxicity study conducted in cynomolgus monkeys, 3 of 28 animals administered 
IMO-8400 at dose levels ≥ 6 mg/kg/week were found dead or sacrificed moribund during the 
study with necropsy findings of myocardial degeneration/necrosis, glomerulonephritis, and/or 
hepatocellular necrosis.  These findings correlated with changes in serum complement levels. 
Alterations in serum complement in these animals were noted in the weeks to months preceding 
their unscheduled deaths. 
If at any time during study participation, a patient experiences an acute drop in complement 
(50% hemolytic complement assay [CH50], complement component 3 [C3], or complement 
component 4 [C4]) levels ≥ 50% or a drop to an absolute value below the lower limit of normal 
with reference to baseline testing or most recent values on study, the following procedures and 
testing should be performed: 
1. Hold study drug treatment 
2. Repeat the serum complement test to confirm decreased complement levels 
3. Query patient for recent change in signs or symptoms suggestive of a rheumatologic or 
vasculitic event, i.e. recent appearance of a rash or bruising, new onset symptoms such as 
fever, arthralgias, or fatigue 
4. Perform physical examination  with careful attention to findings suggestive of vasculitis; 
i.e., rash, palpable purpura, petechiae 
5. Perform repeat complete blood count (CBC) with platelets, or review most recent 
CBC/platelets 
6. Perform repeat urinalysis, or review most recent urinalysis with special attention to 
findings suggestive of glomerulonephritis; i.e., presence of protein, blood, red blood cell 
casts or white blood cell casts  
7. Perform an ECG 
Based on the results of this work-up and the patient’s disease assessment/response to study drug, 
the Investigator in discussion with the Sponsor’s medical monitor, will determine the patient’s 
risk/benefit profile and discuss appropriate next steps regarding the patient’s continued 
participation in the study. 
6.5.5. 
Procedures for Assessment of Patients with Symptomatic Thrombocytopenia 
Severe thrombocytopenia has been reported in clinical studies with another oligonucleotide [25]. 
Most of these patients had confirmed anti-platelet antibodies. These cases occurred 14 to 
26 months after the onset of treatment, suggesting that risk increases with duration of exposure. 
In the event of a precipitous drop in platelet counts (i.e., to <25 x 109/L), treatment with 
IMO-8400 should be held and an anti-platelet antibody count obtained. Treatment can be 
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resumed once pre-treatment criteria (Section 8.4.1) are met. Antiplatelet, thrombolytic, or 
anticoagulant drugs should be used with caution. 
6.5.6. 
Classification of Patients at Termination of Treatment 
To provide for consistent accounting of patient disposition, when study treatment is discontinued 
in an individual patient for any reason, the Investigator will complete the appropriate electronic 
case report form (eCRF) and select the primary reason from the following standard categories:  
• DLT event – defined above.  
• Disease progression – as defined above.  
• Adverse Event, other than DLT – This includes any AE (clinical or laboratory; serious 
or non-serious; regardless of relation to study drug), that represents the reason study 
drug was discontinued, including:  
− The medical judgment of the Investigator based on the best interests of the 
patient.  
− The patient’s request based on any AE.  
• Withdrawal of Consent – The patient desired to withdraw from further participation in 
the study in the absence of a clinical issue.  If the patient gave a reason for 
withdrawing (e.g., leaving area), it should be recorded in the eCRF. 
• Lost to Follow-Up – The patient stopped coming for visits.  
• Study Termination – by the Sponsor, for any reason.  
When study treatment is discontinued for any reason, the End-of-Treatment (EOT) and 
End-of-Study (EOS) visits will be performed as specified (see Section 1.4).  If a patient cannot 
be seen, attempts will be made to contact the patient by telephone to inquire about reasons for 
stopping participation and get updated information on any unresolved AEs.  
6.6. 
Criteria for Replacement Patients  
6.6.1. 
Definition of a Evaluable Patient 
A patient will be considered evaluable for purposes of DRC review if they meet either of the 
following criteria:  
• Received at least 1 dose of study drug and had treatment discontinued because of a 
DLT event as defined in Section 6.3.1; or 
• Received all doses of study drug in the first 4 weeks of treatment and completed 
Week 5 assessment procedures. 
See Section 12 for additional discussion of analysis for safety and efficacy.  
6.6.2. 
Replacement Patients  
A patient who does not meet criteria for “evaluable” may be replaced to assure the requirements 
for completing the cohort are met.  Replacement patients will be identified by distinctive patient 
numbers and will receive the same dose level as the patient being replaced.  
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6.7. 
Maximum Number of Patients and Maximum Exposures 
The maximum exposures to IMO-8400, the investigational agent in this study, will be as follows:  
• Maximum number of patients: Approximately 60 patients in planned escalation and 
expansion cohorts; potential for additional patients in contingency cohorts or as 
replacements. 
• Maximum dose level: Undefined (pending dose escalation results). The planned dose 
escalation cohort levels for IMO-8400 are 0.6, 1.2, 2.4, and 3.6 mg/kg administered 
once weekly and 1.2 mg/kg administered twice weekly 
• Maximum duration of exposure: undefined (treatment is until study completion or 
until the patient experiences intolerable toxicity, disease progression, or withdraws 
consent, whichever comes first as defined in Section 6.10.2.2). 
6.8. 
Treatment Assignment 
See Section 9.3. 
6.9. 
Criteria for Study Termination 
The study ends approximately 6 months following enrollment of the last patient.  The Sponsor 
reserves the right to discontinue or suspend the study earlier for safety or administrative reasons 
at any time, at an individual site or overall.  Should the study be terminated and/or the site closed 
for whatever reason, all study documentation must be archived and study medication must be 
destroyed according to local policy or returned to the Sponsor or its representative per Sponsor’s 
instructions. 
If the trial is terminated prematurely or suspended, the Sponsor will promptly inform the 
participating Investigators and institutions, the regulatory authorities, and the Institutional 
Review Board (IRB) of the termination or suspension and the reason(s) for the action. 
6.10. 
Discussion of Study Design and Treatment Regimens 
This protocol represents the first clinical trial of IMO-8400 in patients with B-cell malignancies 
and the third clinical trial of IMO-8400 overall. 
6.10.1. 
Rationale for Study Structure 
The open-label study design is consistent with both the study objectives and current principles 
for the evaluation of investigational drugs in patients with advanced malignancy.  
The dose escalation design with enrollment guided by safety experience and reviewed by a DRC 
are standard for a Phase 1 study and serve to minimize the number of patients required and to 
assure patient safety is protected. 
The expansion cohorts will permit preliminary signal-seeking and guide further development of 
IMO-8400 in oncology/hematology. 
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6.10.2. 
Rationale for Treatment Regimens in Current Protocol 
6.10.2.1. Dosing Regimen 
Starting dose/Safety.  The proposed starting dose (0.6 mg/kg/week) is consistent with the safety 
experience in protocol 8400-001, the Phase 1 study, in which that dose was administered for 
4 weeks without incident to healthy volunteers; and in protocol 8400-201, the Phase 2a study, in 
which that dose was administered for 12 weeks to patients with moderate to severe plaque 
psoriasis.  The primary TEAEs observed were mild injection sites reactions; there were no 
treatment-related changes in laboratory studies, including tests of liver and renal function.  
Dosing interval. Once and twice weekly dosing are supported by animal studies of autoimmune 
diseases and in vivo tumor growth. 
Dose escalation. Numerically larger increases in hemoglobin and a faster time to response were 
seen in patients dosed at the highest dose level studied in the current trial [24].  In the absence of 
dose-limiting toxicity, further dose escalation to determine the extent of disease control that can 
be attained is appropriate and consistent with standard oncology Phase 1 trial design. 
6.10.2.2. Duration of Treatment 
Treatment with IMO-8400 will continue until study completion or until the patient experiences 
intolerable toxicity, disease progression, or withdraws consent, whichever comes first.   
Follow-Up.  Additionally, patients who have discontinued study treatment for reasons other than 
progressive disease will be assessed per Response Assessment in WM from the VIth International 
Workshop, at a minimum of every 12 weeks (± 4 weeks) until documentation of progressive 
disease, start of new anti-cancer therapy, or until study completion, for up to 6 months from the 
last patient’s first treatment (Cycle 1, Day 1), whichever comes first. 
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7. 
SELECTION OF PATIENTS 
7.1. 
Source of Patients and Recruitment Methods 
Following receipt of IRB approval, the Investigator may initiate patient recruitment (see 
Section 13).  To reach an economically and socially diverse population, the study may be 
announced in newspapers and on relevant Internet websites; prior to use, the form and content of 
such announcements will be submitted to the IRB for approval (see Section 13). 
7.2. 
Patient Restrictions during the Conduct of the Study  
In the interest of their safety and to facilitate assessment of both safety and treatment effect, the 
patients participating in this study will be requested to agree to the following restrictions during 
the study:  
• Not start any new prescription medications, except as prescribed or approved by their 
Investigator or if required in an emergency; 
• Not take any over-the-counter medications, except as instructed or approved by their 
Investigator.  
 
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8. 
STUDY TREATMENT  
8.1. 
Study Treatments to be Administered 
All patients will receive the investigational study drug, IMO-8400, at the weekly exposure level 
designated for the cohort in which they are enrolled.  Instructions for dose preparation are 
provided in the Pharmacy Manual. Weekly exposure levels are calculated as mg/kg based on 
body weight at Screening. The dose is to be recalculated if change in body weight from 
Screening exceeds 10% (±). Dose volume per injection site should not exceed 1.2 mL/site, with 
multiple sites used per dose as necessary. 
8.2. 
Description and Manufacture of Study Drug 
All manufacture, packaging and labeling operations will be performed according to Good 
Manufacturing Practice (GMP) and Good Clinical Practice (GCP) guidelines, as well as 
US regulations.  
Table-9.  
Physical and Chemical Properties of Active Ingredient (Drug Substance) 
Name 
IMO-8400  
Drug Class 
Oligonucleotide antagonist of TLRs 7, 8 and 9 
INN 
NA 
Molecular Formula 
C179H216N52Na17O101P17S17 (sodium salt) 
Molecular Weight 
6174 (sodium salt) 
Appearance 
hygroscopic white to off-white amorphous solid obtained by lyophilization 
Solubility 
freely soluble in aqueous media 
Melting Point 
amorphous powder, decomposes without a defined melting point. 
Abbreviations:  INN=international nonproprietary name; NA=not applicable; TLR=Toll-like receptor 
Table-10.  Formulation of IMO-8400 for Injection (Drug Product) 
Name 
IMO-8400 for Injection, 150 mg 
Active ingredient 
IMO-8400 
Excipients 
Each vial contains nitrogen (National Formulary). 
How supplied 
Sterile, lyophilized powder for reconstitution packaged in a clear, round 5-mL glass vial with a 
rubber stopper and aluminum overseal. Each vial contains 150 mg IMO-8400 free acid, as 
labeled, corrected for moisture and impurities. 
Storage 
The sealed vials of formulated drug product should be stored at 2-8°C. 
Preparation and 
handling 
Vials are reconstituted using Sterile Saline or Sterile Water for Injection, USP (to be provided 
by study site). The choice of diluent and the reconstitution volume are determined by the vial 
strength and the dose level assigned; see Pharmacy Manual for details.  
Administration 
The dose is administered as SC injection(s), not to exceed 1.2 mL/site, with multiple sites 
used per dose as necessary, using a fresh sterile needle (approximately 26 g); see 
Section 8.4 regarding the site of injection. 
Abbreviations:  SC=subcutaneous; USP=United States Pharmacopeia 
8.3. 
Reconstitution of IMO-8400 for Injection  
Detailed dose-preparation instruction and flow-sheets are provided in the Pharmacy Manual.  
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8.4. 
Administration of Study Treatments 
Each dose of IMO-8400 will be administered as SC injection(s), not to exceed 1.2 mL/site, with 
multiple sites used per dose as necessary. For example, a 1.5 mL dose volume would be 
administered as two separate injections of 0.75 mL.  The injection sites should be selected based 
on the following:  
• Areas for injection are the 4 quadrants of the abdomen (upper and lower on the left 
and right) and the upper thigh of each leg. 
• Injection sites should be rotated, that is, no injection area used more than once every 
6 injections.  
In the event these guidelines cannot be accommodated due to injury or other issue, the 
Investigator should discuss the situation with the Idera Medical Monitor. 
8.4.1. 
Pre-Treatment Criteria 
IMO-8400 should not be administered until the following conditions are met: 
• Hemoglobin ≥7.5 g/dL 
• ANC ≥1,000/µL 
• Platelets ≥50,000/µL 
• All other laboratory abnormalities to baseline or grade ≤1 
These parameters will be measured at local laboratories at Week 1 and Week 5 of each cycle. 
8.4.2. 
Variances in Dose Administration Schedule 
Once weekly dosing: for patients assigned to dose levels of 0.6, 1.2, 2.4, or 3.6 mg/kg/week.  
The expectation is that patients will be dosed each week on the same day of the week.  To allow 
for holidays and other scheduling issues, individual doses may be administered up to 2 calendar 
days earlier or later than expected, while remaining on the same schedule.  Doses should not be 
administered fewer than 5 calendar days after the preceding dose.  
If, for any reason (e.g., scheduling or toxicity), dosing is interrupted more than 2 calendar days 
beyond expected, then the next dose should be administered as soon as feasible and the schedule 
reset to once weekly on the next convenient weekday. 
Twice weekly dosing: for patients assigned to the dose level of 1.2 mg/kg twice weekly 
(2.4 mg/kg/week). The total weekly exposure will be administered as a 2 separate SC injections 
of 1.2 mg/kg per injection, respectively, over the course of the week.  The expectation is that 
patients will be dosed twice each week on the same day of the week, with (approximately) 72 or 
96 hours (3 or 4 calendar days, respectively) between injections.  The minimum interval between 
successive doses may not be less than 48 hours (2 calendar days).  If, for any reason 
(e.g., scheduling or toxicity), the interval between successive doses is 6 or more calendar days, 
then the next dose should be administered as soon as feasible and the twice weekly dosing 
schedule resumed. 
Extended dosing interruptions.  If, for any reason, dosing is interrupted for more than 
21 calendar days due to toxicity, the patient should be discontinued from study treatment unless 
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the Investigator and the Idera Medical Monitor agree that it is in the patient’s best interest to 
continue.  
8.5. 
Assigning Patients to Treatment Groups  
See Section 9.3.  
8.6. 
Prior and Concomitant Medications 
Prior treatments for WM will be recorded in the eCRF as well as treatments for any significant 
illness in the past year.  
Any concomitant medication used from time of Screening through last study visit will be 
recorded in the eCRF, including dose, dosage regimen, and indication (reason for its 
prescription).  
8.6.1. 
Prohibited Treatments 
The exclusion criteria specify treatments prohibited at the time of study entry (Section 1.5.3).  
While patients are receiving study treatment, other treatments for WM are prohibited.  Patients 
who discontinue treatment prematurely and have completed the EOT visit, may receive available 
or investigational treatment for their disease at any time based on the judgment of their 
physician.  If such treatment is initiated prior to the EOS visit (scheduled for 30 days after last 
dose of study drug), this will be recorded in concomitant medications and considered in 
assessment of any new AEs.  
8.6.2. 
Other restrictions 
None. 
8.7. 
Treatment Compliance  
All doses of study drug will be administered by study personnel.  Injections of study drug may be 
administered in one of two contexts:  
• Study site – defined as the site designated by the participating Investigator.  On Study 
Days when a Physical Examination is scheduled (that is, at Day 1 and at the first 
weekly doses of Weeks 2 and 5 of Cycle 1 and at Weeks 1 and 5 of additional 
cycles), it is expected that study drug will be administered at the study site.  
• Non-study site administration by a visiting nurse – With the agreement of the patient 
and the Investigator, doses not administered at the study site may be administered by 
a visiting nurse who has been trained in the protocol and approved by the Sponsor. 
− The Sponsor will arrange for a Central Pharmacy to prepare and dispense the 
patient’s study treatment, which will be packaged as required and shipped by 
overnight delivery service.  To protect the integrity of the treatment, the shipping 
container must be held unopened in a cool, dry, protected place. 
− The visiting nurse will open the container, inspect the materials, confirm they are 
correct, and proceed with pre-dose procedures, study drug administration, and 
post-dose procedures. 
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− The used syringe and packaging materials will be disposed of per policy of the 
Central Pharmacy.  
− The visiting nurse will maintain appropriate source documents; the events will be 
entered into the electronic data capture (EDC) system and copies of the source 
documents provided to the site. 
8.8. 
Accountability of Investigational Drug Supplies 
Study drug will be provided by the Sponsor.  The Investigator at each study site is responsible 
for the control of the study drug, and will identify trained and experienced personnel to handle it 
in accordance with the protocol and appropriate GCP and GMP principles (Central Pharmacy 
will be responsible for study drug stored at Central Pharmacy and dispensed to the patient).  This 
includes:  
• Storing the drug in a secure, controlled-access location. 
• Storing the drug under the specified conditions, including daily monitoring and 
recording of storage temperature. 
• Maintaining records of the receipt of study drug and providing acknowledgement of 
receipt. 
• Dispensing and administering study drug only in accordance with the protocol. 
• Maintaining drug accountability records indicating the disposition of study drug, 
including a Drug Dispensing Log containing the following information: 
− Identification of the patient to whom the study drug was dispensed. 
− Date(s) and quantity of the study drug dispensed to the patient.  
• Having all records and drug supplies available for inspection by the study monitor.  
8.8.1. 
Disposition of Study Drug 
At any time during or after completion of the study, the site must obtain written authorization 
from the Sponsor regarding the final disposition of any remaining study drug; that disposition 
must be appropriately documented.  Typical procedures for handling any remaining study drug 
include the following: 
• Returning study drug to the Sponsor.   
• Destroying study drug at the study site according to the site’s institutional standard 
operating procedure. 
 
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9. 
STUDY EVENTS AND EVALUATIONS 
9.1. 
Schedule of Events 
The schedule for all study events is detailed in Table-4.  Table-5 gives an estimate of blood 
volumes required.  
The schedule is presented relative to the day and time of dosing.  All Days are relative to the 
calendar day of the first injection of study drug, designated Day 1.  All weeks are relative to 
Week 1 of each cycle, defined as Day 1 through Day 7, inclusive.  All times are relative to 
injection, designated 0 hour; “pre-dose” vital signs are to occur within 1 hour prior to injection; 
all other pre-dose procedures are to occur prior to injection on the same calendar day.  
9.2. 
Screening Procedure 
The screening evaluation may be performed up to 21 days prior to dosing.  Written informed 
consent will be obtained before any study-specific procedures are performed.  The consent 
procedure must be recorded in source documentation.  All patients who sign an informed consent 
form (ICF) will be entered into the EDC system within 48 hours of consent.  To minimize patient 
risk and discomfort, the radiologic imaging and bone marrow biopsy scheduled at Screening will 
be performed only after the patient meets all other inclusion and exclusion criteria.  
Waldenström’s macroglobulinemia is a rare disease and patients often travel considerable time 
and distance to be managed at tertiary referral centers.  To facilitate rapid completion of 
screening and enrollment and thereby avoid the need for multiple trips, Investigators may, with 
the approval of the Sponsor, perform screening laboratory studies at their local laboratory, 
including safety labs (see Section 9.7), cryoglobulins and cold agglutinins, and qualifying total 
serum IgM and monoclonal serum IgM protein levels (see Section 9.4.2).  In such cases, central 
laboratory tests scheduled at Screening will be handled as follows:  
• Concurrent safety labs (see Section 9.7) will not be submitted to the central lab.  
• Blood and urine samples will be submitted to the central lab for the tests relating to 
monoclonal protein (see Section 9.4.2) and to Investigational studies (see Section 9.9) 
to support longitudinal data analysis.  
Pre-dose on Day 1, safety labs will be sent to the central laboratory for all patients as scheduled 
and used as the baseline (pre-treatment) safety laboratory values to support longitudinal analysis.  
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9.3. 
Enrollment Procedure 
The following procedure is to assure that patients enrolled across multiple sites are assigned to 
the appropriate cohort and receive the appropriate dose level.  Patients who have completed all 
screening procedures and are assessed as eligible by the Investigator will be reviewed with the 
Sponsor or the Sponsor’s designated representative.  After acceptance, the Investigator and site 
pharmacy will be provided the following information in writing (by email and/or fax):  
• The patient’s assigned unique study number, to be marked on all study-specific 
documents.  
• The patient’s assigned dose level.  
9.4. 
Assessments of Waldenström’s Macroglobulinemia  
Laboratory assessments for disease status (see Section 9.4.2) will be conducted at Screening, 
every 4 weeks ± 1 week (Week 1 and Week 5 of each cycle), every 12 weeks ± 4 weeks during 
the Follow-up Phase, at the EOT visit, and at the EOS visit.   
Clinical assessments for disease status (see Section 9.4.1) will be conducted at Screening, every 
8 weeks ± 1 week (Week 1 of every cycle), every 12 weeks ± 4 weeks during the Follow-up 
Phase, at the EOT visit, and at the EOS visit.   
Radiologic imaging will be performed at Screening and at EOT visit or as clinically indicated.  
Bone marrow biopsy and aspirate will be performed at Screening, EOT, and to document 
complete response as appropriate (see Section 16.2).    
A medical history specific to WM will be collected at Screening and will include, but is not 
limited to: a detailed review of the patient’s malignancy, prior treatments, relevant current or past 
abnormalities or diseases, and signs and symptoms of WM at baseline (Section 9.6.1). 
9.4.1. 
Clinical Assessments  
• ECOG performance status.  
• Clinical assessment for tumor status including assessment of lymphadenopathy, 
hepatomegaly and splenomegaly.  
9.4.2. 
Laboratory Assessments Relating to Total IgM and Monoclonal Protein  
The following laboratory assessments will be performed by a central laboratory approved by the 
Sponsor.  As noted above, patients being enrolled on the basis of local lab data may be qualified 
based on local results for serum IgM monoclonal protein levels, but at the time of Screening they 
will still have blood and urine samples submitted so that the panel below may be performed at 
the central lab.  
• Total serum IgM by nephelometry (i.e., total IgM or IgM). 
• Quantification of serum IgM monoclonal and total protein by densitometry, 
i.e., Serum Protein Electrophoresis with immunofixation (i.e., monoclonal IgM or 
M-spike). 
• Serum Free Light Chains (sFLC) and ratio. 
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• Serum β2-microglobulin. 
• Serum viscosity. 
• Urine Free Light Chains (uFLC) and ratio. 
9.4.3. 
Radiologic Imaging 
Computed tomography or magnetic resonance imaging scan of chest, abdomen and pelvis to 
assess for lymphadenopathy and organomegaly.  Modality of the scan must be consistent 
throughout the study.  Interim scans may be performed at the request of the Investigator and with 
the approval of the Idera Medical Monitor based on new signs or symptoms.  
9.4.4. 
Bone marrow biopsy and aspirate 
The procedures for collecting, processing, and transporting bone marrow biopsy and aspirate 
specimens will be detailed in the Bone Marrow Biopsy manual.  Bone marrow biopsy and 
aspirate specimens will be sent to the central pathologist for confirmation of disease status, flow 
cytometry, and to the central laboratory for investigational studies of tumor cells (see 
Section 9.9).  The percent lymphoplasmacytic cell involvement will be noted for each biopsy 
performed.  Bone marrow biopsy and aspirate will be performed at Screening, EOT, and to 
document complete response as appropriate (see Section 16.2). 
9.5. 
Evaluation of Response to Treatment and Disease Status 
The criteria for response to treatment are provided in Section 16.2 (based on the full text of the 
VIth International Workshop classification [1]). Central laboratory serum total IgM and serum 
monoclonal IgM values are to be used to evaluate response to treatment (refer to Section 9.4.2). 
The Third International Workshop for WM also defined the following categories [26]:  
Not evaluable response: Reserved for situations in which there is insufficient data for a 
determination of response to treatment.  
Delayed response: A delayed response is described particularly after treatment with purine 
analogue or monoclonal antibody.  The recommendation was that patients should be followed for 
at least 12 weeks after treatment initiation to be considered unresponsive to therapy.  
9.6. 
General Clinical Assessments 
9.6.1. 
Medical History, including WM 
At the Screening visit, the Investigator will obtain a comprehensive medical history to ensure 
eligibility of the patients, including the following items:  
• A detailed review of the course of the patient’s malignancy, including clinically 
significant complications such as systemic infections, bleeding events, etc. 
• Prior treatments, including supportive therapy (agent, duration, best clinical response, 
AEs related to treatment, and reason for discontinuation). 
• Relevant current or past abnormalities or diseases (including surgical procedures) of 
the following systems: allergic (including drug sensitivity), cardiovascular, 
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dermatologic, endocrine/metabolic, gastrointestinal, gynecologic, 
hematologic/lymphatic, hepatic/biliary, immunologic, infectious, musculoskeletal, 
neurologic/psychiatric, renal, and respiratory. 
• A separate eCRF will be provided to record signs and symptoms of WM at Baseline, 
including but not limited to: bleeding events, fatigue, anemia, thrombocytopenia, 
leukemia/neutropenia, fever, hyperviscosity, neuropathy, lymphadenopathy, weight 
loss, headache, night sweats, and vision changes. 
Past history should include all significant illnesses that the patient has experienced and have 
resolved within the 12 months prior to signing informed consent.  Illnesses active at the time of 
informed consent will be regarded as concomitant illnesses.  Concomitant illnesses that worsen 
or illnesses with onset after obtaining informed consent will be recorded on the AE form in the 
EDC (see Section 10), with particular attention to whether the onset was before or after 
administration of the first dose of study drug.  If a WM sign or symptom recorded at Screening 
worsens, it will be captured as an AE. 
9.6.2. 
Physical Examination and Body Weight 
Complete physical examinations will include examination of general appearance, skin, neck 
(including thyroid), eyes, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, 
reproductive (in event of recent history, symptoms or AEs related to reproductive system) and 
nervous system and measurement of body weight.  Exam of reproductive system when needed 
may be performed by the Investigator or delegated to a specialist. 
Height and weight will be evaluated at Screening and the body mass index will be calculated. 
Any clinically significant changes in physical exam identified after obtaining informed consent 
will be recorded using the AE form in the EDC (see Section 10). 
9.6.3. 
Vital Signs 
Vital signs include heart rate (HR), blood pressure (BP), respiratory rate, and temperature.  
Where feasible, vital signs should be measured before blood is drawn and after the patient has 
been sitting comfortably for 5 minutes with the BP cuff in place on the non-dominant arm.  
Blood pressure and HR measurements will be taken first and may be done manually or by 
automated recorder. Respiratory rate will be determined by observation for at least 30 seconds.  
Temperature will be obtained using an electronic (rapid reading) device.  
Vital sign measurements will be assessed by the Investigator as either ‘normal,’ ‘abnormal, not 
clinically significant,’ or ‘abnormal, clinically significant.’  Clinically significant abnormal vital 
sign measurements will be reported as an AE, and, if possible, should be repeated at clinically 
relevant intervals until resolved or stabilized.  
9.6.4. 
Electrocardiogram  
Standard 12-lead ECG will be obtained after the patient has been semi-recumbent for 
~10 minutes. The following ECG parameters will be recorded: ventricular rate, RR interval, PR 
interval, QRS interval, QT interval, QTc interval, and QTc method. Electrocardiograms are to be 
performed at Screening, at pre-dose and 2 hours post-dose on Day 1 of Cycle 1, and pre-dose at 
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the first dosing visit of Weeks 1 and 5 of each cycle thereafter. In addition, an ECG is to be 
performed at 2 hours post-dose on Day 1 of each odd-numbered cycle. 
9.6.5. 
Injection Site Reaction (ISR) Assessments 
Injection site reactions will be documented in detail for each individual injection as described in 
Table-11.   Each ISR shall also be captured on the AE form in the eCRF. 
The Investigator will assess the injection site as scheduled and perform the following:  
• Pain, tenderness, pruritus and induration: grade using the scale provided;  
• For induration, also record the actual maximal linear diameter as a continuous 
variable;  
• Erythema, record the actual maximal linear diameter as a continuous variable;  
• Blisters, ulceration, necrosis: indicate presence or absence and record the maximal 
linear diameter, if applicable.  
Table-11. IMO-8400 Subcutaneous Injection Site Grading (Local Reactions) 
Finding 
Mild 
Moderate 
Severe 
Pain 
Present; no limitations in 
ADL 
Limitations in age-appropriate 
instrumental ADL  
or requires repeated non-narcotic 
pain reliever 
Limitations in self-care ADL 
or interferes with sleep,  
or requires repeated narcotic 
pain reliever 
Tenderness 
Mild discomfort with 
pressure 
Discomfort with touch 
Discomfort elicited by clothing 
or bedsheets 
Pruritus 
(itch) 
Present, but minimally 
distracting 
Present, distracting during routine 
activities 
Interferes with sleep 
Induration  
(swelling, edema) 
Present; no limitations in 
ADL 
Limitations in age-appropriate 
instrumental ADL  
or requires repeated treatment 
(excluding systemic steroids). 
Limitations in self-care ADL 
or requires treatment with 
systemic steroids 
Pain: discomfort or unpleasant feeling (e.g., headache) experienced while at rest or with activity; in addition to location, the 
patient’s description may include intensity as well a distinctive quality (e.g., burning, stabbing).  
Tenderness: discomfort elicited when the area is touched either intentionally or accidently.  
Pruritus (itch): an unpleasant sensation that evokes the desire or reflex to scratch. (In contrast, pain and tenderness evoke a reflex 
to withdraw.) 
Activities of daily living (ADL) are classified into two subsets:  
– instrumental ADL, e.g., preparing meals, shopping for groceries or clothes, using the telephone, managing money;  
– self-care ADL, e.g., bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not being 
bedridden. 
When reporting injection site reactions as an AE, the Investigator should report in the verbatim 
term the words “injection site reaction,” along with the specific reaction symptom (such as 
erythema), and select the severity grade based on the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) guidelines which are presented in 
Table-12. 
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Table-12. Intensity of AE of Injection Site Reactiona 
Mild 
Moderate 
Severe 
Life-threatening 
Tenderness with or without 
associated symptoms  
(e.g., warmth, erythema, itching) 
Pain;  
lipodystrophy;  
edema;  
phlebitis 
Ulceration or necrosis; 
severe tissue damage; 
operative intervention indicated 
Life-threatening 
consequences;  
urgent intervention 
indicated 
a. Based on NCI-CTCAE v.4.03. Definition of Injection Site Reaction: A disorder characterized by an intense adverse reaction 
(usually immunologic) developing at the site of an injection. 
9.7. 
Safety Laboratory Studies 
The laboratory tests indicated below will be performed by a central laboratory designated by the 
Sponsor (except for sites approved to use local laboratory results for screening as detailed in 
Section 9.2).  The procedures for collecting, processing, and transporting the required blood 
samples will be detailed in the laboratory manual.  
The Investigator may order additional local laboratory tests consistent with their routine standard 
of care.  
9.7.1. 
Safety Laboratory Tests  
Hematology Panel  
*Hemoglobin  
*Hematocrit  
*Red blood cell count (RBC) 
*White blood cell (WBC) count  
*Platelet count  
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Mean corpuscular volume (MCV) 
*WBC differential (absolute cell counts): 
- Neutrophils  
- Lymphocytes  
- Monocytes  
- Eosinophils  
- Basophils  
Clinical Chemistry Panel 
*Glucose  
*Urea  
*Creatinine 
*Sodium 
*Potassium 
*Chloride 
*Bicarbonate  
C-reactive protein (CRP) 
Magnesium 
Calcium  
Phosphate  
Uric Acid 
Cholesterol  
Triglycerides 
Low density lipoprotein (LDL)  
High density lipoprotein (HDL) 
*Alanine aminotransferase (ALT) 
*Aspartate aminotransferase (AST) 
*Alkaline phosphatase (AP) 
*Total bilirubin  
Total protein  
Albumin  
Lactate dehydrogenase (LDH) 
Creatine phosphokinase (CK) 
* Laboratory tests comprising focused panel to be performed on Weeks 3 and 7 of each cycle.  
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Serum Complement Testing 
Complement component 3 (C3) 
Complement component 4 (C4) 
50% hemolytic complement (CH50) 
Coagulation Panel 
Prothrombin Time (PT) 
Activated partial thromboplastin time (aPTT) 
International normalized ratio (INR) 
Fibrinogen 
Urinalysis 
Specific gravity, pH, ketones, glucose, protein, blood (commercial dipstick may be used);  
microscopic examination, including quantitation of white blood cells and red blood cells. 
Serologic tests (Screening only) 
Hepatitis B surface antigen (HBsAg) 
Antibody to human immunodeficiency 
virus (HIV)-1 and HIV-2 
Antibody to hepatitis C virus (HCV) 
Pregnancy tests (Females only) 
beta-human chorionic gonadotropin (β-hCG) 
9.7.2. 
Reporting of Safety Laboratory Tests 
Results of safety laboratory tests are expected to be available to the Investigator within 48 hours. 
Procedures for the Investigator assessment of the results are detailed in Section 10.2.  Procedures 
for the analysis of laboratory data are described in Section 10.4.5.  
9.7.3. 
Repeating Abnormal Laboratory Tests 
Laboratory tests showing abnormal or exclusionary values at Screening may be repeated no more 
than once.  After dosing, abnormal laboratory tests assessed as “clinically significant” values 
may be repeated as often as deemed clinically necessary by the Investigator until the test values 
are clinically acceptable or until an explanation other than drug effect is given.  
9.8. 
Pharmacokinetic Assessments 
Blood samples for plasma levels of IMO-8400 will be collected as scheduled.  Samples will be 
analyzed for IMO-8400 concentration using a validated bioanalytical method (estimated 
sensitivity, 20 ng/mL).  Pharmacokinetic data will be analyzed on an individual basis.  
For each cohort, the plasma IMO-8400 concentration data will be analyzed by 
non-compartmental PK analysis. The following parameters will be determined as appropriate: 
observed maximum plasma concentration (Cmax), time of Cmax (Tmax), and AUC from 0 to last 
measurable plasma concentration (AUC0-t).  Pharmacokinetic parameters will be compared 
across IMO-8400 dose levels. Descriptive statistics will be provided for all PK parameter values 
by dose and time, as appropriate. 
9.9. 
Investigational Laboratory Studies 
The following laboratory studies relate to assessing the pharmacologic effects of the 
investigational agent.  Samples will be collected as scheduled and sent to the Central Lab, where 
they will then be sent to Sponsor-designated qualified labs for testing.  The clinical significance 
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of these tests is unknown at this time and therefore the results will not be assessed by the 
Investigator.  
Tumor cells from the bone marrow biopsy samples will be assayed for:  
• Presence of MyD88 L265P mutation, and, if indicated, other somatic mutations in 
genes encoding proteins in the TLR and BCR signaling pathways (e.g., CARD11, 
IRAK4, BTK).  Samples will be retained for up to 1 year after completion of the 
study to support possible future development of a companion diagnostic assay. 
Serum samples will be assayed for:  
• Levels of cytokines IL-6, IL-12, IL-17, IP-10; additional or alternative cytokines may 
be assessed using the samples collected.  
• Antibodies to IMO-8400.  
• NF-κB pathway inhibition.  
 
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10. 
SAFETY ASSESSMENTS (ADVERSE EVENTS) 
10.1. 
Definition of Adverse Events 
10.1.1. 
Adverse Event  
An AE is any untoward medical occurrence temporally associated with the use of a medical 
product in a patient, whether or not the event is considered causally related to the medical 
product.1  An AE can be a new occurrence or an existing process that increases significantly in 
intensity or frequency.   
An AE in a clinical trial may be any of the following:  
• Unfavorable and unintended symptom reported by the patient — patients will be 
encouraged to report TEAEs spontaneously; general, non-directed questioning may 
also be used to elicit reports of AEs;  
• Clinical sign detected by the Investigator — observations by other study personnel 
will be reported to the Investigator for evaluation;  
• Abnormal result from a laboratory study or other diagnostic procedure that meets at 
least one of the following criteria:  
− Results in termination of study drug; 
− Leads to treatment;  
− Leads to further diagnostic tests (other than a single repeat for confirmation);  
− Is assessed as “clinically significant” by the Investigator (see Section 10.2).  
10.1.2. 
Serious Adverse Event  
An AE is serious when the patient outcome is one or more of the following: 
• Death.  
• Life-threatening, meaning that the patient was at immediate risk of death from the 
event at the time that the event occurred.  It does not include an event which 
hypothetically might have caused death if it occurred in a more severe form.  
• Hospitalization, initial or prolonged, meaning that a hospital admission and/or 
prolongation of a hospital stay was required for the treatment of the AE, or occurred 
as a consequence of the event.  It does not include a pre-planned elective hospital 
admission for treatment or diagnostic procedures, or, in general, a hospital admission 
of less than 24 hours duration.  
• Disability or incapacity that is persistent or significant.  
1 A medical product may be a drug or a device being used either prior to or after regulatory approval. The medical 
product in this protocol will hereafter be referred to as study drug (synonym: investigational agent).  
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• Congenital anomaly or birth defect.  
• Important medical event that, although not immediately life-threatening, requires 
intervention in order to prevent one of the other serious outcomes listed above.  
Examples of such events are allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; blood dyscrasias or convulsions that do not result in 
hospitalization; or the development of drug dependency or drug abuse.  
10.1.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
A SUSAR is defined as an SAE that meets both the following criteria with respect to study drug:  
• Suspected — is assessed as related or possibly related to study drug (see 
Section 10.4.3);  
• Unexpected — compared to the study drug-related AEs described in Investigator’s 
Brochure, the event meets any of the following criteria: 
− The event was not previously described;  
− The event is now characterized as more severe (see Section 10.4.4);  
− The event is now characterized more specifically (e.g., an event of “interstitial 
nephritis” in a patient receiving an agent previously described as associated with 
“acute renal failure”). 
In clinical trials involving ill patients, events considered related to the natural history of the 
disease under study or to lack of efficacy (that is, the event is considered more likely related to 
those factors than to other factors, including study drug) are not considered "unexpected."  Lack 
of efficacy is recorded as specified elsewhere in the Protocol.  
10.2. 
Investigator Assessment of Safety Laboratory Tests 
The Investigator will review the results of all Safety Laboratory tests (see Section 9.7.2) and 
designate any results outside of the reference range as either of the following:  
• Abnormal, not clinically significant (NCS). 
• Abnormal, clinically significant (CS).  
In making this judgment, the Investigator will consider all available information, including the 
patient’s clinical condition, all available laboratory results (central and local), and the potential 
for false positive test results.  In addition, laboratory studies that result in the actions specified in 
Section 10.1.1 will be classified as CS.  
Any result assessed as CS will be recorded as an AE unless it is consistent with one or more of 
the following:  
• Process noted in the medical history. 
• Ongoing AE already recorded.  
• Expected course of the primary disease under study.  
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10.3. 
Recording Adverse Events 
Procedures for the collection and recording of AEs are as follows:  
• From obtaining informed consent through EOS, there will be active surveillance to 
identify all AEs.  Events will be recorded in the AE portion of the EDC, with 
particular attention to whether the onset of the event was before or after the 
administration of the first dose of study drug.  All recorded events will be included in 
applicable line listings, but only events with onset after administration of the first 
dose will be included in summaries of TEAEs (see Section 12.2).   
• After the EOS, surveillance will be passive (only events brought to the Investigator’s 
attention will be considered) and only events assessed as SUSARs will be recorded 
(see Section 10.1.3). 
• In accordance with the FDA guidance document – Safety Reporting Requirements for 
Investigational New Drugs (INDs) and Bioavailability/Bioequivalence (BA/BE) 
Studies – disease progression does not require reporting as an AE or SAE. However, 
signs and symptoms related to disease may be reported at the discretion of the 
Investigator.  
10.4. 
Characterizing Adverse Events 
For each AE recorded the following characteristics will be noted.   
10.4.1. 
Description of Event  
The diagnosis or description will be as specific and complete as possible (i.e., “lower extremity 
edema,” rather than just “edema”).  Whenever possible, signs and symptoms due to a common 
etiology will be reported as an integrated diagnosis; for example, cough, runny nose, sneezing, 
sore throat and head congestion would be reported as “upper respiratory infection.”  
10.4.2. 
Date and Time of Onset  
The date and time at which the event was first apparent. Table-13 summarizes the basis for 
reporting the date and time of onset for the different types of AEs.  
Table-13.  Reporting the Date and Time of Onset of adverse events for Different Types of Events  
Type of Event 
Examples 
Source of Date and Time of Onset 
Symptom 
Headache, feverish, paresthesiae  
When first experienced by the patient 
Sign (Finding) 
Elevated blood pressure, enlarged liver 
on physical exam 
When first observed by the Investigator or other 
study staff 
Laboratory/ 
diagnostic result 
Neutropenia, hyperglycemia,  
lesions on brain scan 
When lab sample was obtained or diagnostic study 
performed 
The time of onset of symptoms may be appreciably earlier than the date and time the Investigator 
becomes aware of the event.  Some events may be apparent to the patient and Investigator 
independently, and information from each may contribute to the final report.  For example, a 
patient may report the onset of a rash 2 days before being seen by a physician who makes a 
diagnosis of herpes zoster based on appearance and laboratory confirmation.  In that case, there 
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is a single AE, with the date of onset based on the date of the initial observation by the patient 
and a specific description (herpes zoster) based on the clinical exam and tests.  
10.4.3. 
Relationship to Study Drug 
This determination is based on the Investigator’s clinical judgment regarding the likelihood that 
the study drug caused the AE and may include consideration of some or all of the following 
factors:  
• Alternative possible causes of the AE, including the patient’s underlying disease or 
co-morbid conditions, other drugs, other host and environmental factors. 
• Temporal sequence between the exposure to study drug and the AE.  
• Whether the clinical or laboratory manifestations of the AE are consistent with known 
actions or toxicity of the study drug.  
• Whether the AE resolved or improved with decreasing the dose or stopping the study 
drug (i.e., dechallenge); or recurred or worsened with re-exposure to the drug 
(i.e., rechallenge).  
The relationship between the study drug and the AE will be described using one of the following 
categories:  
• Related — the study drug is more likely the cause of the AE than other factors;  
• Possibly related — there is a reasonable possibility that the study drug is the cause of 
the AE, including that the study drug and another factor(s) are equally likely as 
causes of the AE;  
• Unlikely related — another factor is considered more likely the cause of the AE than 
the study drug;  
• Not related — another factor is considered to be the cause of the AE.  
Related and possibly related AEs may result during the use of the study drug as planned (per 
protocol), or from abuse, withdrawal or over-dosage of the agent.  
10.4.4. 
Severity 
The severity of clinical AEs (i.e., symptoms reported by the patient and/or signs observed by the 
Investigator) will be assessed using the guidelines summarized in Table-14 [27]. 
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Table-14.  Estimating Severity Grade 
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 activities of daily livinga 
Grade 3/Severe 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
livingb 
Grade 4/Life-threatening 
Life-threatening consequences; urgent intervention indicated 
Grade 5/Death 
Death related to adverse event 
a. Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, ect. 
b. Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
10.4.5. 
Grading of Laboratory Safety Tests for Reporting and Analysis 
Treatment-emergent abnormal laboratory results will be handled as follows: 
• Graded using NCI-CTCAE Version 4.03 criteria 
• Assessed as potential DLT events based on pre-specified criteria (see Section 6.3.1)  
• Reported as AEs when assessed as “clinically significant” using the procedures and 
criteria detailed in Section 10.2. 
10.4.6. 
Management of Study Drug upon Occurrence of an Adverse Event 
For each AE the Investigator will indicate which one of the following actions regarding the 
administration of study drug was taken because of that AE:  
• Discontinued (withdrawn) — study drug was stopped permanently due to the AE. 
• Dosing Interrupted — study drug regimen was modified by being temporarily halted, 
i.e., 1 or more doses were not administered, but drug was not stopped permanently. 
• Dose Decreased — study drug regimen was modified by subtraction, i.e., by 
decreasing the frequency, strength or amount. 
• None — no change in the administration of study mediation.  
For patients whose treatment is paused and then resumed at a lower dose level as detailed in 
Section 6.5.2, the management of study drug will be recorded as “Dose Decreased.” 
10.4.7. 
Actions Taken for Management of AE 
Adverse events will be followed and managed by the Investigator, including obtaining any 
supplemental studies needed to define the nature and/or cause of the event (e.g., laboratory tests, 
diagnostic procedures, consultation with other health care professionals).  
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For each AE the Investigator will categorize as follows the actions taken to manage the AE:  
• Concomitant medication — 1 or more medications (prescription or over-the-counter) 
were started or increased in dose; non-medication actions may also have been 
ordered.  
• Other action — only non-medication action(s) were ordered as management of the 
AE (e.g., bed placed in Trendelenburg position, warm compresses applied to SC 
access site).  
• No action — no actions were ordered for management of the AE.  
10.4.8. 
Follow-up and Outcome of AEs 
If possible, AEs will be followed until resolved (synonyms: recovered, recuperated, ended) either 
with or without sequelae, including for patients who prematurely discontinue study participation.  
For AEs that are assessed as not drug-related and are not resolved at the EOS visit, follow-up 
may be limited with the approval of the Medical Monitor.  
The outcome of each event will be described using the following categories:  
• Resolved without sequelae — the event resolved and patient returned to baseline.  
• Resolved with sequelae — the event resolved but the patient is left with residual 
problems (e.g., functional deficits, pain).  
• Resolving — at the last observation, the event was improving.  
• Not Resolved — at the last observation, the event was unchanged.  
• Death (Fatal) — to be used for the one AE which, in the judgment of the 
Investigator, was the primary cause of death.  
• Unknown — there were no observations after the onset (initial observation or report) 
of the event.  
Note: Resolving and Not Resolved may also be used for AEs that were unresolved at the time a 
patient died, but were not assessed as the primary cause of death. 
10.4.9. 
Date and Time of Outcome  
For each class of outcome as defined above, Table-15 indicates the date and time to be recorded. 
As discussed in detail for date/time of onset (see Section 10.4.2), determining the date/time an 
event resolved (ended) should reflect the type of event and the source of the information.  
Table-15.  Date and Time of Outcome for Adverse Event by Outcome Class  
Outcome assigned to Adverse Event 
Date and Time to be Recorded 
Resolved (with or without sequelae) 
Date and time event observed or reported as resolved 
Death 
Date and time of death 
Resolving or Not Resolved 
Date and time of last observation 
Unknown 
None (see definition above) 
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10.5. 
Reporting Adverse Events 
10.5.1. 
Where to Report SAEs  
Serious AE reporting will be performed by the site using the EDC system; detailed training will 
be provided during site initiation.  Reports and supporting materials relating to SAEs will be 
scanned and uploaded into the EDC system.  Contact information for the Medical Monitor and 
the Pharmacovigilance services is provided in Table-1 and Table-2. 
In the event a SAE cannot be submitted via EDC, contact information is provided in Table-1 for 
alternative submission methods.  
10.5.2. 
Procedures for Reporting SAEs to the Sponsor  
The initial notification of each SAE will be entered into the EDC system within 24 hours of the 
time the Investigator (or the Investigator's designee) becomes aware that the event has occurred.  
The following items will be entered into the appropriate EDC section (any items not available 
should be explicitly noted):  
• Protocol number, study site, patient number.  
• Investigator’s name and contact information (phone, email).  
• Description of the event (i.e., date and time of onset, initial assessment, treatments 
and course).  
• Current status of the patient and the event.  
• Criteria by which the event was assessed as serious.  
• Date of the first injection of study drug.  
• Date of the last injection of study drug prior to the event.  
• Assessment of relationship of study drug to the event.  
• Whether the study drug was discontinued or adjusted as a result of the event.  
The following additional information will be entered within 2 days for death and life-threatening 
events and within 4 days for all other SAEs;  
• Narrative summary of the event — to include specific information that will assist in 
understanding the event, e.g., relevant medical history, co-morbid conditions, 
physical exam, diagnostics, assessment, treatments (including concomitant 
medications), response to treatment, course, and outcome (if known); 
• Copies of relevant medical reports — including diagnostic procedures 
(e.g., laboratory, ECG, x-ray), surgical procedures, and consultations.  
Additional documentation may be submitted as part of a follow-up report. 
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10.5.3. 
Other Reportable Events 
Certain events that occur in the absence of an AE should be reported to the Sponsor. These 
include the following: 
• Pregnancy exposure (patient becomes pregnant while taking study drug). Should a 
female patient or partner of a male patient become pregnant during the study, the 
patient will inform the Investigator. The patient will be asked to follow up with the 
study site to report the eventual outcome of the pregnancy. The information will be 
tracked by the Sponsor.  
• Lactation exposure (patient was taking study drug while nursing an infant). 
• Accidental exposure (someone other than the patient was exposed to study drug).  
• Overdose (patient received more than the prescribed dose of study drug within a 
given timeframe).  
• Other medication errors that potentially place patients at greater risk of harm than was 
previously known or recognized (e.g., study drug was administered via incorrect 
route). 
10.5.4. 
Requirements for Expedited and Periodic Reporting of Adverse Events  
Suspected unexpected serious adverse reactions are required to be reported rapidly to regulatory 
authorities and to IRBs (typically within 7 days for fatal or life-threatening SUSARs; within 
14 days for all other SUSARs).  The Sponsor and the Investigator will work together to meet 
these reporting requirements.  
10.5.5. 
Notification of SAEs to the Investigator by the Sponsor  
In accordance with regulatory requirements, the Sponsor or designee will notify the Investigator 
of the occurrence of SUSARs reported by other Investigators in this or in other studies involving 
the study drug.  The Investigator will promptly inform his/her IRB of such communications from 
the Sponsor and will document that notification in the Investigator’s Regulatory Binder.  
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11. 
DATA QUALITY ASSURANCE 
11.1. 
Compliance 
The Sponsor and the Investigator will conduct the study in accordance with:  
• The protocol — as approved by applicable regulatory authorities;  
• Ethical standards and procedures — as detailed in Section 13;  
• “Good Clinical Practices” and “Good Manufacturing Practices” — as detailed in 
documents issued by the International Council for Harmonisation (ICH); 
• Applicable national regulations — e.g., in the US, 21 Code of Federal Regulations 
(CFR).  
• FDA guidance document: Safety Reporting Requirements for INDs and BA/BE 
Studies 
11.2. 
Training and Qualifications of Site Personnel  
All site personnel involved in the study will be trained regarding the protocol and the study drug.  
This includes, but is not limited to, pharmacy, nursing and medical personnel involved in 
handling and administering the study drug, monitoring the patients and collecting clinical data.  
The Sponsor (or designee) will provide formal training sessions either off-site (e.g., Investigators 
Meeting) or on-site (e.g., site initiation visit).  Topics covered will include, but not be limited to, 
background of the investigational drug, the protocol, study events, study procedures, data 
collection and recording, expedited and routine reporting of AEs, and regulatory requirements.  It 
is the responsibility of the Investigator to document that all participating study personnel have 
received adequate training.  
11.3. 
Source Documents  
Source documents are the originals of any documents used by the Investigator, hospital, or 
institution that verify the existence of the patient and substantiate the integrity of the data 
collected during the trial.  Medical records related to the patient’s routine clinical care, including 
prior to or during the study:  
• Information obtained from the patient’s personal physicians or other third parties 
regarding the patient’s medical history or prior physical condition. 
• Medication prescription and administration records.  
• Laboratory reports, including clinical pathology and diagnostic histologic pathology.  
• Reports of imaging studies. 
• Data and reports from automated instruments (e.g., ECGs, cardiac monitors, vital 
signs).  
• Medical records relating to scheduled and unscheduled clinical visits. 
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It is expected that Investigator’s clinical practice will include medical records that meet current 
best practices for readability and documentation.  Electronic health record (EHR) systems should 
meet current regulatory requirements for “protected health information,” including, at a 
minimum, security requirements for electronic signature and audit trails for changes.  
11.3.1. 
Study-Specific Source Documents 
Study-specific source documents include, but are not limited to, the following: 
• The ICF, signed and dated by the patient. 
• The site screening log.  
• Any clinical reports noted above that are scheduled as part of the protocol and have 
been annotated to indicate the significance of any abnormal findings (see 
Section 10.4.5). 
• Concomitant medication prescription and administration records.  
• Records relating to scheduled and unscheduled study visits, including, but not limited 
to, results of examinations, observations relating to AEs, and concomitant 
medications.  
Study-specific source documents must meet the following requirements:  
• Be prepared at the time of the events or activities described (i.e., contemporaneously);  
• Indicate both the date and time recorded;  
• Identify the source of all recorded information (e.g., the patient, direct observations of 
the recorder, lab reports, external / historical sources); 
• Text should be readable and unambiguous, including application of best medical 
record practices (e.g., minimal use of abbreviations; proper numerical, dose and 
posology formats);  
• Entries will be signed and dated by the recorder.  
Study-specific paper documents must meet the following additional requirements: 
• Be written legibly in dark (preferably black) ink, including signature and date;  
• In the event that any entry needs to be changed, a single line will be made through the 
original entry, the correct information added next to it, and the action initialed, dated, 
and explained (if appropriate).  The original entry must not be obscured or obliterated 
by multiple cross-out, correction fluid or overlay of other material.  
Study-specific source document forms created by the site must be reviewed by the Sponsor prior 
to use. 
11.4. 
Electronic Case Report Forms  
The Sponsor will provide a regulatory-compliant EDC system for reporting study data to a 
central facility holding the trial database.  All study personnel will be trained on the system and 
each will have a unique login password and electronic signature.  
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The Investigator (or qualified sub-Investigator approved by the Sponsor) will review all eCRFs 
and indicate their concurrence by (electronic) signature.  
11.5. 
Protocol Deviations 
A protocol deviation is defined as an event in which the Investigator or site personnel did not 
conduct the study according to the Protocol, including compliance requirements and agreements.  
Guidelines for minor procedural variations (e.g., collection time of blood samples) will be agreed 
to and documented by the Investigator and the Sponsor prior to starting the study.  Events 
conforming to those guidelines will not be considered deviations.  
For protocol deviations relating to individual patients, the event and relevant circumstances will 
be recorded on source documents and on the appropriate eCRF; reported to the Sponsor in a 
timely manner; and presented in the Clinical Study Report (CSR).  
Deviations that are not patient-specific (e.g., unauthorized use of an investigational agent outside 
the protocol, either human administration or laboratory use) will be reported to the Sponsor in 
writing and copies placed in the Trial Master File (TMF).  
Deviations that can be anticipated should, if possible, be discussed with the Sponsor before being 
implemented. 
11.6. 
External Review of the Study Conduct at Participating Sites 
All study-related materials at the site are subject to external review to ensure the safety of the 
patients, the integrity of the study data, and compliance with all applicable regulatory and 
oversight requirements. 
There are several different classes of review: 
• Monitoring — review by the Sponsor or authorized representatives, typically from the 
contract research organization (CRO) coordinating the clinical conduct of the trial.  
As detailed below, visits may be conducted before, during, and after the conduct of 
the study. 
• Audits — systematic, independent review by the quality assurance department of the 
Sponsor or authorized representatives, potentially from an organization not involved 
in the clinical conduct of the study;  
• Regulatory review — performed by representatives of regulatory authorities with 
responsibility for oversight of the trial or approval of the investigational agent. These 
authorities may be from the country where the site is located or from another country.  
Monitoring and auditing visits on behalf of the Sponsor will be scheduled with the Investigator 
in advance and will be conducted at a reasonable time.  To facilitate these visits, the Investigator 
will assure that the following are available: 
• Appropriate space, facilities and access to all source documents (including access to 
computerized records either electronically or as complete print outs).  
• Consent forms, eCRFs, SAE forms, and medical records for all screened and enrolled 
patients.  
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• Timely access to site personnel, including the Investigator, sub-Investigator(s), and 
other study personnel on the day of the visit to resolve any questions that arise. 
Regulatory authorities may visit and review the site and/or Investigator during or after the study 
and may or may not notify the Investigator or the Sponsor in advance.  The Investigator will 
fully cooperate with regulatory audits conducted at a reasonable time in a reasonable manner.  
The Investigator will notify the Sponsor immediately of any contact by or communication from 
regulatory authorities regarding the study.  
11.7. 
Study Monitoring Visits 
11.7.1. 
Site Qualification and Initiation Visits 
Before an investigational site can enter a patient into the study, a representative of Idera 
Pharmaceuticals, Inc. will visit the site to perform the following: 
• Inspect the facilities (e.g., clinical and administrative areas, pharmacy, laboratory).  
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, as well as the responsibilities of Idera Pharmaceuticals, Inc. 
and its representatives.  
• Review the site TMF, including documentation related to the protocol, the 
Investigator, and other study site personnel; correspondence to and from the IRB, the 
Sponsor, and their representatives.  
• Review the standard operating procedures and current practices relating to clinical 
and pharmacy activities, data handling, the IRB oversight and the informed consent 
process. 
11.7.2. 
Interim Monitoring Visits 
During the study, a monitor from or representing Idera Pharmaceuticals, Inc. will visit the 
investigational site, for the following:  
• Provide information and support to the Investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product is being 
appropriately handled and accounted for. 
• Perform source data verification, including verifying the data in the eCRFs against 
the relevant source documents (see Section 11.3) and resolving any discrepancies 
noted.  
• Record and report any protocol deviations.  
• Confirm that AEs and SAEs have been properly documented on eCRFs; that any 
SAEs have been forwarded to Idera Pharmaceuticals, Inc.; and that SAEs meeting 
criteria for reporting have been forwarded to the IRB.  
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Between visits the monitor will be available as needed to provide information or support to the 
Investigator(s) or other staff. 
11.7.3. 
Study Closeout Visit 
The study will be considered complete when all of the following have occurred:  
• All treated patients have completed all scheduled visits plus any unscheduled 
follow-up required by AEs;  
• All eCRFs have been completed, submitted and all queries resolved;  
• The trial database has been locked.  
The Sponsor or designee will then conduct a study closeout visit, which may include, but is not 
limited to, the following:  
• Review the site TMF to assure all required regulatory documents are current and 
complete.  
• Resolve any open issues from prior monitoring, audit or inspection visits.  
• Review the site’s provisions for meeting the requirements for retention study records.  
• Discuss possible future site audits.  
• Review the Sponsor’s publication policy.  
• Confirm compliance with requirements for notifying the IRB of study events, 
including closure.  
• Collect any unused study materials for either return to the Sponsor or disposal in a 
manner approved by the Sponsor.  
11.8. 
Resolution of Deficiencies  
The Investigator agrees to take promptly any reasonable steps requested by the Sponsor to 
resolve any deficiencies identified as a result of monitoring, audits, inspections, protocol 
deviations, or review of any other study documentation.  Failure to take adequate remedial action 
can result in suspension or termination of the study at the site. 
11.9. 
Retention of Records 
All study-related materials at the site (e.g., source documents, eCRFs, TMF) will be retained 
according to ICH guidelines and applicable regulations.  
The study drug is being developed under a US Investigational New Drug application; regulations 
require all study-related materials be retained for at least 2 years after one of the following 
events: 
• Approval of a New Drug Application based on this study.  
• Notification by the Sponsor that no further application will be filed.  
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The Investigator will use the following procedures regarding retained records:  
• Contact the Sponsor before destructing any records pertaining to the study. 
• Provide the Sponsor an opportunity to collect the records.  
• Obtain written permission from the Sponsor to destroy the records.  
• Notify the Sponsor if the Investigator plans to leave the institution so that 
arrangements can be made for the transfer of records.  
Clinical and laboratory samples that are unstable may be disposed with the written approval of 
the Sponsor.  
11.10. 
Data Management  
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12. 
STATISTICS 
The sections below indicate the overall structure and approach to the analysis of this study.  A 
detailed Statistical Analysis Plan (SAP) incorporating these sections below will be prepared 
separately and approved by the Sponsor.  The SAP will define populations for analysis, outline 
all data handling conventions, including software, and specify additional statistical methods to be 
used for analysis of safety, efficacy, and PK.  
12.1. 
Sample Size Determination and Study Power 
Following identification of the MTD/RP2D, up to an additional 22 patients will be enrolled at the 
MTD or proposed RP2D level.  With a total sample size of 22 patients, there is a 90% probability 
to detect an AE with a true incidence rate of 10%.  A secondary objective of this study is to 
determine the treatment effect of IMO-8400 in patients enrolled at the MTD/RP2D.  Using the 
exact binomial distribution with a 1-sided test and an alpha of 0.05, there is 79% power to detect 
a response rate of 33% as compared to a null response rate of 10%. 
12.2. 
Analysis Populations 
Safety/Intent-to-treat (ITT) Population — all patients who received at least 1 dose of study 
treatment. 
Efficacy Evaluable (EE) Population – all patients who completed ≥1 cycle of therapy or those 
who discontinued due to progressive disease or DLT. 
Per-Protocol (PP) Population — all patients who have adequate data at baseline and at 1 or 
more scheduled post-treatment tumor assessment and have no major protocol deviations.  For 
patients who discontinue study treatment for any reason and start another treatment of their 
malignancy, no subsequent response assessments will be used for efficacy evaluation.  
12.3. 
Analysis of Safety  
Safety analyses will be conducted on the Safety/ITT Population.  Safety observations will be 
analyzed using descriptive statistics and tabulation.  No formal statistical comparisons are 
planned. All safety data will be presented in listings.  
• Safety Endpoints 
− AEs. 
− Concomitant medications. 
− Clinical observations (e.g., vital signs, physical examination). 
− Laboratory tests, (e.g., clinical chemistry, hematology, coagulation, urinalysis). 
− ECGs. 
− Injection site reactions. 
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• Analyses  
− TEAEs: by dose level, intensity, and relationship to investigational product.  
− Treatment-emergent changes in severity grade of laboratory tests (see 
Section 10.4.5) will be summarized as “shift tables.” 
− Descriptive statistics will be summarized for vital signs and ECG parameters by 
dose level and visit. 
− Concomitant medications will be summarized by WHO Drug Class and ATC text. 
− Injection site reactions will be summarized by incidence for each dose group and 
overall by worst grade on study.  Time-to-event analyses will be performed for 
injection site reactions. 
12.4. 
Analysis of Treatment Effect 
Analyses of treatment effect will be performed on both the EE and PP populations. 
12.4.1. 
Assessments 
Laboratory assessments for disease status (see Section 9.4.2) will be conducted at Screening, 
every 4 weeks ± 1 week (Week 1 and Week 5 of each cycle), every 12 weeks ± 4 weeks during 
the Follow-up Phase, at the EOT visit, and at the EOS visit.  Clinical assessments for disease 
status (see Section 9.4.1) will be conducted at Screening, every 8 weeks ± 1 week (Week 1 of 
every cycle), every 12 weeks ± 4 weeks during the Follow-up Phase, at the EOT visit, and at the 
EOS visit.  Radiologic imaging will be performed at Screening and at EOT visit or as clinically 
indicated.  Bone marrow biopsy and aspirate will be performed at Screening, EOT, and to 
document complete response as appropriate (see Section 16.2).  
12.4.1.1. Primary Treatment Effect Parameter 
The primary treatment effect parameter is objective response rate, defined as the occurrence of 
CR, VGPR, PR, or MR.  
12.4.1.2. Secondary Treatment Effect Parameters 
The VIth International Workshop specifies a number of outcome metrics related to time [1] (see 
Section 16.3).  The following parameters are considered most relevant to this time-limited study 
and will be analyzed both globally across all cohorts and by dose level.  
• Distribution of response categories by treatment group and overall. 
• Time to progression – Time from the initiation of treatment to disease progression 
with deaths due to unrelated causes censored.  
• Progression-free survival – Time from the initiation of treatment to disease 
progression or death from any cause. 
• Time to best observed response – Time from the initiation of treatment to best 
observed category of response. 
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• Percent and absolute change in quantitative serum levels of monoclonal and total 
IgM.  
Kaplan-Meier analyses will be used to analyze time to event data.  Analysis of IgM data will be 
performed using a repeated measures mixed model.  MyD88 L265P mutation status will be used 
as a covariate in statistical analyses. 
12.5. 
Exploratory Analyses 
The following investigational factors will be analyzed with regard to disease status:  
• Presence or absence of MyD88 L265P mutation in tumor cells. 
• Serum cytokine levels.  
• Serum levels of antibody to IMO-8400. 
• NF-κB inhibition. 
12.6. 
Identification of Study Event Days and Times 
Study events will be recorded using the calendar date and (where applicable) the time to the 
nearest minute.  
For purposes of post-study analysis (e.g., tables and listings), study days will be designated as 
follows:  
• Day 1 is defined as the calendar day of the first injection of study drug.  
• The days prior to Day 1 are designated Day –1, Day –2, etc; there is no Day 0.  
• The days following the day of the first injection of study drug are designated Day 2, 
Day 3, etc. 
• The day of the last injection of study drug is indicated by adding the suffix "L," 
e.g., if the last injection is administered on Day 43, it will be displayed as "Day 43L." 
• The days following the last injection of study drug are designated Day 1P, Day 2P, 
etc.  
The times of events related to dosing of study drug will be designated as minutes or hours before 
or after the time of dosing (i.e., the SC injection of study drug), which is designated as t = 0 
(zero).  Thus, 15 minutes prior to dosing is t = –15 min; 2 hour after dosing is designated t = 2 h.  
12.7. 
Handling Missing Data 
Missing data will not be imputed.  In time-to-event analyses using Kaplan-Meier methodology, 
patients who do not experience the event of interest will be censored.  Rules for censoring of data 
will be described in the SAP.  Further details for handling of missing, duplicated or unscheduled 
data will be given in the SAP.  
12.8. 
Changes in the Planned Analyses 
If changes to the analyses planned in the protocol are made, then these will be listed in the CSR, 
along with an explanation as to why they occurred.  
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13. 
ETHICAL CONSIDERATIONS 
The study will be conducted in accordance with: 
• the current version of “Ethical Principles For Medical Research Involving Human 
Subjects” as adopted by the World Medical Association (WMA)[28];2  
• local laws and regulations for the use of investigational therapeutic agents.  
13.1. 
Independent Ethics Committee (IEC) 
13.1.1. 
Initial Review Prior to Study Initiation  
Prior to initiating the study, the Investigator will submit the following to an IEC3 for approval: 
• Study protocol; 
• Investigator’s Brochure; 
• ICF and any other written documents to be given to the patient; 
• Details of any compensation to participants;  
• Copies of any proposed public announcements of the trial (e.g., advertisements, web 
postings); 
• Any other requested document(s). 
The study will not commence until the IEC has issued a letter of approval signed and dated by 
the IEC chair or authorized person which includes the following items:  
• Protocol number, full title, version number and date;  
• Version date of the ICF;  
• Version date of the applicable Investigator’s Brochure;  
• Date the protocol and consent form were reviewed and approved by the IEC.  
2 This document, commonly referred to as the “Declaration of Helsinki”, was issued in 1964 and has been amended 
or clarified at subsequent WMA Assemblies. Only the current document is considered official by WMA. The 
most recent version was approved in October 2013 (Fortaleza, Brazil).  
3 ICH E6, which specifies GCP, requires “an independent body (a review board or a committee, institutional, 
regional, national or supernational) …. whose responsibility it is to ensure the protection of the rights, safety, and 
well-being of human subjects involved in a trial…” In this protocol, the body performing this function will be 
referred to as the IEC (Independent Ethics Committee); in practice, many alternative designations are used, e.g., 
Institutional Review Board (IRB).  
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The Sponsor or designee will be provided copies of all correspondence between the Investigator 
and the IEC.  In addition, prior to study initiation, the Sponsor will be provided one of the 
following to verify that the IEC was appropriately qualified to approve the protocol: 
• Documentation that on the date of the approval, the IEC met all currently applicable 
regulatory requirements for policies and procedures (e.g., membership, quorum, and 
approval procedures);  
• A memo listing the voting members of the IEC who were present at the meeting the 
protocol was approved, including their titles, occupations, and institutional 
affiliations.  
13.1.2. 
Subsequent Submissions to the IEC  
After the initial approval, the Sponsor and Investigator will submit the following to the IEC: 
• Any new information that may be relevant to a patient’s willingness to initiate or 
continue participation in the trial; 
• Any proposed amendments to the protocol;  
• Proposed revisions to the ICF that incorporate new information or procedures;  
• Copies of any proposed public announcements of the trial;  
• At least annually, a report of the study’s progress;  
• Notification of any decision by the Investigator or Sponsor to suspend or terminate 
the study and the reason(s) for such action.  
13.2. 
Written Informed Consent 
Informed Consent Forms submitted to the IEC must be (a) based on a master document provided 
by the Sponsor and (b) reviewed and approved by the Sponsor prior to submission to the IEC.  
The Sponsor must also review and approve any changes requested by the IRB prior to the ICF 
being used. 
Informed consent will be obtained prior to conducting any study procedures that are not part of 
the patient’s routine medical care.  During the consent process, each patient will:  
• Be advised of the nature and risk of the study by the Investigator or designated study 
personnel;  
• Be given sufficient opportunity to read the ICF, to ask any questions, and to consider 
whether to participate;  
• Provide informed consent voluntarily.  
The ICF will be signed and dated by the patient and by the person who provided the information.  
A copy of the signed ICF will be provided to the patient; the original will be retained by the 
Investigator as a source document.  The informed consent process will be noted in the source 
documents.  
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The patient will be informed in a timely manner if new information becomes available that may 
be relevant to the patient’s willingness to continue participation in the trial.  Communication of 
this information to the patient will be noted in the source documents. 
13.2.1. 
Obtaining Informed Consent from Patients Who Are Not Literate 
If a patient is not literate, then ICF must be signed (or marked) by the patient and signed by an 
impartial witness who was present during the entire informed consent process.  
Note that this process is not applicable to patients who are literate in a language other than 
English; they must be provided an approved, certified translation of the ICF in that language. 
13.2.2. 
Special Informed Consent Situations Not Applicable to This Protocol  
Patients may not be enrolled if they meet any of the following conditions which require specific 
provisions and approvals not provided for in this protocol:  
• Are not able to provide informed consent (e.g., are acutely or permanently impaired);  
• Are at increased risk of coercion (e.g., prisoners, institutionalized persons);  
• Are less than 18 years of age.  
13.2.3. 
Protection of Patient Information 
The identity and collected data of each patient (“protected health information”) will be kept 
confidential and will be protected in accordance with applicable local regulations.  
Methods to be used to protect the data will include the following:  
• Each patient will be assigned a unique patient number, which will be used on the 
eCRF in place of the patient’s name.  
• Computer systems for collecting and analyzing the data will have restricted access.  
• In publications, aggregate data will be used wherever possible; any individual data 
will be redacted of unique identifying characteristics.  
The informed consent process will comply with local requirements relating to (a) disclosure of 
the data to be collected and (b) authorization for its use.  When permitted, these issues will be 
included in the ICF.  In the event a separate form is required, the following will apply: 
• The Sponsor must review and approve the separate form. 
• The form will be signed and dated by, and copies provided to, the required parties.  
• A completed copy of the form will be placed in the trial files with the completed ICF.  
 
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14. 
 STUDY ADMINISTRATION 
14.1. 
Registration of Study 
The Sponsor will register the trial on clinicaltrials.gov in accordance with applicable US 
regulatory requirements and the guidelines of the International Committee of Medical Journal 
Editors (ICMJE) regarding registration of controlled clinical trials (“clinically directive trials”).  
14.2. 
Changes in the Conduct of the Study  
After the protocol has been approved by the governing IEC and regulatory authority, substantial 
changes in the conduct of the study will only be made as formal protocol revisions, which must 
be reviewed and approved by the Sponsor and the Investigator prior to submission to the 
applicable IEC and regulatory body.  Changes will only be implemented after the revised 
protocol is approved as required. 
Changes to contract information or designated study personnel (page 3) may be handled 
administratively.  
14.3. 
Confidentiality 
This protocol, the applicable Investigator’s Brochure, the results of the study and other related 
information provided by the Sponsor represent confidential and proprietary material of the 
Sponsor.  They will be available only to the Investigator, personnel directly involved in the 
study, and authorized members and staff of the applicable IEC.  These parties agree not to 
disclose these materials to others.  
14.4. 
Financial Disclosure 
In compliance with US 21 CFR 54.4, any listed or identified Investigator or Sub-Investigator 
(including the spouse and any dependent children of said individuals) directly involved in the 
treatment or evaluation of research patients will disclose the following information for the time 
period during which the Investigator is participating in the study and for 1 year following 
completion of the study: 
• Any financial arrangement between Idera Pharmaceuticals, Inc. and the Investigator 
in which the value of the compensation to the Investigator for conducting the study 
could be impacted by the outcome of the study. 
• Payments (exclusive of the costs of conducting this or other clinical studies) by Idera 
Pharmaceuticals, Inc. totaling > $10,000, including, but not limited to, grants to fund 
ongoing research, compensation in the form of equipment, retainer for ongoing 
consultation, or honoraria. 
• Any proprietary interest held by the Investigator in the product being evaluated. 
• Equity interest in Idera Pharmaceuticals, Inc. that exceeds $10,000, including 
ownership interest, stock options, or other financial interest whose value cannot be 
determined through reference to public prices.  
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14.5. 
Publication Policy 
The information developed during the conduct of this clinical study is considered confidential by 
Idera. This information may be disclosed as deemed necessary by Idera. 
To allow for the use of the information derived from this clinical study and to ensure compliance 
with current regulations, the Investigator is obliged to provide Idera with complete test results 
and all data developed in this study. The information obtained during this study may be made 
available to other physicians who are conducting similar studies and to the FDA or other 
regulatory authorities. Such information may be disclosed as deemed necessary by Idera. 
Idera intends that the data from this study will be presented and published. The Idera staff in 
collaboration with the Investigator will be responsible for writing presentations and manuscripts 
for publication. Investigators will not be allowed to publish or present the data from this study 
without prior agreement with Idera. 
14.6. 
Authorship and Acknowledgement 
All publications will give Idera Pharmaceuticals, Inc. and/or their personnel appropriate credit 
(i.e., authorship or acknowledgement) for any direct contribution made by them. 
Authorship will be decided jointly by the Investigators and the Sponsor. Manuscripts will 
conform to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 
including, but not limited to, the standards for authorship contained therein. 
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15. 
LIST OF REFERENCES 
1 Owen RG, Kyle RA, Stone MJ, et al. Response Assessment in Waldenström’s 
Macroglobulinemia: update from the VIth International Workshop. Br J Haematology 2012; 
160:171-176.  
2 Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s 
macroglobulinemia. N Engl J Med. 2012;367(9):826–833. 
3 Young RM, Staudt LM. Targeting pathologic B cell receptor signaling in lymphoid 
malignancies. Nature Rev Drug Discovery. 2013; 12:229-243. 
4 Lim K-H, Barton GM, Staudt LM. Oncogenic MYD88 mutants require Toll-like receptors. 
Amer Assoc Cancer Res, 2013 Annual Meeting, Abstract 2332. 
5 Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological Definition of Waldenström’s 
Macroglobulinemia: Consensus Panel Recommendations from the Second International 
Workshop on Waldenström’s Macroglobulinemia. Sem. Oncol. 2003; 30: 110-115.  
6 Dimopoulos MA, Gertz, MA, Kastritis E, et al. Update on Treatment Recommendations from 
the Fourth International Workshop on Waldenström’s Macroglobulinemia. J Clin Oncol. 
2008; 27: 1-8. 
7 Treon SP. How I treat Waldenström macroglobulinemia. Blood. 2009;114(12):2375-85. 
8 Johnson SA, Birchall J, Luckie C. Guidelines on the management of Waldenström’s 
Macroglobulinemia. Br J Haematol. 2006;132:683-97. 
9 Green N, Marshak-Rothstein A. Toll-like receptor driven B cell activation in the induction of 
systemic autoimmunity. A Sem Immunol. 2011; 23:106-112.  
10 Marshak-Rothstein A, Rifkin I. Immunologically Active Autoantigens: The Role of Toll-Like 
Receptors in Development of Chronic Inflammatory Disease. Ann Rev Immunol. 
2007;25:419-441. 
11 Sun S, Rao N, Venable J, et al. TLR7/9 Antagonists as Therapeutics for Immune-Mediated 
Inflammatory Disorders. Inflamm Alerrgy Drug Targets. 2007; 6:223-235. 
12 Cros J, Cagnard N, Woollard K, et al. Human CD14dim Monocytes Patrol and Sense Nucleic 
Acids and Viruses via TLR7 and TLR8 Receptors. Immunity. 2010; 33:1-12. 
13 Demaria O, Pagni P, Traub S, et al. TLR8 deficiency leads to autoimmunity in mice. J Clin 
Invest. 2010; 120:3651-3662. 
14 Choi JW, Kim Y, Lee J-H, Kim Y-S. MYD88 expression and L265P mutation in diffuse large 
B-cell lymphoma. Hum Pathol. 2013; 44:1375-1381. 
15 Wang JQ, Jeelall YS, Horikawa K. Emerging targets in human lymphoma: targeting the 
MYD88 mutation. Blood Lymph Cancer 2013;3:53–61. 
16 Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human 
lymphoma. Nature. 2011;470(7332): 115–119. 
17 Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent 
mutations in chronic lymphocytic leukaemia. Nature. 2011;475(7354):101–105. 
18 Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic 
lymphocytic leukemia. N Engl J Med. 2011;365(26):2497–2506. 
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19 Montesinos-Rongen M, Godlewska E, Brunn A, Wiestler OD, Siebert R, Deckert M. 
Activating L265P mutations of the MYD88 gene are common in primary central nervous 
system lymphoma. Acta Neuropathol. Dec 2011;122(6):791–792. 
20 Gonzalez-Aguilar A, Idbaih A, Boisselier B, et al. Recurrent mutations of MYD88 and 
TBL1XR1 in primary central nervous system lymphomas. Clin Cancer Res. Oct 1, 
2012;18(19):5203–5211. 
21 Li ZM, Rinaldi A, Cavalli A, et al. MYD88 somatic mutations in MALT lymphomas. Br J 
Haematol. 2012;158(5):662–664. 
22 Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma 
incidence patterns by WHO subtype in the United States, 1992–2001. Blood. 2006;107:265-
276. 
23 Ries LAG, Eisner MP, Kosary CL, eds. SEER Cancer Statistics Review, 1975-2001. 
Bethesda, MD: National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2001/. 
Accessed 25 Sept 2013. 
24 Thomas, S, Harb W, Beck T, et al. Interim Results From a Phase 1/2, Open-Label, 
Dose-Escalation Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenström’s 
Macroglobulinemia Abstract, ASH Annual Meeting 2015. 
25 FDA Briefing Document: Peripheral and Central Nervous System Drugs Advisory Committee 
Meeting. NDA 206031. Drisapersen. 2015 Nov. 
26 Kimby E, Treon SP, Anagnostopoulos A, et al. Update on Recommendations for Assessing 
Response from the Third International Workshop on Waldenström’s Macroglobulinemia. Clin 
Lymphoma & Myeloma. 2006; 6: 380-383. 
27 Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0, 28 May 2009. 
U.S. Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. NIH Publication No. 03-5410. 
28 WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human 
Subjects, Available at (accessed 8 October 2013) 
http://www.wma.net/en/30publications/10policies/b3/ 
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16. 
CRITERIA FROM THE INTERNATIONAL WORKSHOPS 
16.1. 
Diagnostic Criteria for Waldenström’s Macroglobulinemia  
The following is reproduced from the “Recommendations from the Second International 
Workshop on Waldenström’s Macroglobulinemia” [5]. 
 
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16.2. 
Classification of Disease Response for Waldenström’s Macroglobulinemia  
Reproduced from Reference [1]. 
 
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16.3. 
Efficacy Measure Definitions 
Reproduced from Reference [1]. 
 
 
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17. 
INVESTIGATOR’S AGREEMENT 
I have read the foregoing protocol (Protocol 8400-401, Version 7.0) and agree to the following: 
• The protocol contains all necessary details for carrying out this study.  
• I will conduct the study as detailed in the protocol and will abide by all its provisions. 
• I will conduct the study in compliance with ICH Guidelines for GCP, the 
requirements of the IRB and all applicable government regulations. 
• I will train and supervise all individuals delegated to assist me in conducting this 
study, including providing copies of the protocol and all pertinent information and 
discussing the material with them to ensure they are fully informed regarding the 
investigational drug, the protocol and their responsibilities and obligations.  
• I will use only the current ICF approved by the Sponsor (or their designee) and by the 
IRB responsible for this study.  
• I will fulfill all requirements for submitting pertinent information to the IRB and to 
the Sponsor, including reportable SAEs.  
• I will complete all case report forms, including resolution of queries, in a timely 
manner.  
• I will provide the Sponsor (or their designee) with access to any source documents 
from which case report form information may have been derived. 
• I will provide the Sponsor with complete, signed statements of financial disclosure as 
required. 
• I understand that the information in this protocol and the referenced Investigator’s 
Brochure is confidential and that its disclosure to any third parties (other than those 
approving or conducting the study) is prohibited. I will take the necessary precautions 
to protect this information from loss, inadvertent disclosure or access by third parties.  
 
 
Signature of Investigator 
 
Date (dd-mmm-yyyy) 
 
Investigator (printed name): 
 
Title: 
 
Address: 
 
 
Facility / Site of Investigation:   
Facility address: 
 
 
 
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SAP_001.pdf: 
Statistical Analysis Plan 
Page 1 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Phase 1/2 Open-label, Multiple-dose, Dose-escalation Study to Evaluate the 
Safety and Tolerability of IMO-8400 in Patients with Relapsed or 
Refractory Waldenström’s Macroglobulinemia 
 
Protocol Number: 
Protocol Version and Date: 
8400-401 
Version 4.0, 22 Sep 2014 
Version 3.0, 23 Jul 2014 
Version 2.0, 18 Nov 2013 
Version 1.0, 11 Oct 2013 
Name of Test Drug: 
IMO-8400 
Phase: 
Phase 1/2 
Methodology: 
Open-label, Multiple-dose, Dose-escalation, Multicenter 
Sponsor: 
Idera Pharmaceuticals, Inc. 
167 Sidney Street 
Cambridge, MA  02139 
Sponsor Representatives: 
Julie Brevard, MPH 
Director of Statistics 
Idera Pharmaceuticals, Inc. 
 
Robert D. Arbeit, MD 
Vice President, Clinical Development 
Idera Pharmaceuticals, Inc. 
Statistical Analysis Plan Date: 
13 January 2015 
Statisitcal Analysis Plan 
Version:  
Final Version 1.0 
 
 
 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Idera 
Pharmaceuticals, Inc. and any unauthorized use or disclosure of such information without the 
prior written authorization of Idera Pharmaceuticals, Inc. is expressly prohibited. 
 
 
 
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TABLE OF CONTENTS 
Section 
Page 
1.
Statistial Analysis Plan Objectives ................................................................................. 8
2.
Information From the Study Protocol ........................................................................... 9
2.1. 
Introduction and Objectives ............................................................................... 9 
2.1.1. 
Introduction ............................................................................................. 9 
2.1.2. 
Study Objectives ..................................................................................... 9 
2.2. 
Study Design ....................................................................................................... 10 
2.2.1. 
Synopsis of Study Design ..................................................................... 10 
2.2.2. 
Stopping Rules ...................................................................................... 12 
2.2.3. 
Data Review Committee (DRC) ........................................................... 13 
2.2.4. 
Study Procedures .................................................................................. 14 
2.2.5. 
Safety, Efficacy, and Pharmacokinetic Parameters .............................. 18 
3.
Subject Population ......................................................................................................... 20
3.1. 
Population Definitions ....................................................................................... 20 
3.2. 
Protocol Deviations ............................................................................................ 20 
4.
General Statistical Methods .......................................................................................... 21
4.1. 
Sample Size Justification ................................................................................... 21 
4.2. 
General Methods ................................................................................................ 21 
4.3. 
Computing Environment................................................................................... 22 
4.4. 
Baseline Definitions ............................................................................................ 22 
4.5. 
Methods of Pooling Data ................................................................................... 22 
4.6. 
Adjustments for Covariates .............................................................................. 22 
4.7. 
Multiple Comparisons ....................................................................................... 22 
4.8. 
Subpopulations ................................................................................................... 22 
4.9. 
Withdrawals, Dropouts, Loss to Follow-up ..................................................... 22 
4.10. Missing, Unused, and Spurious Data ............................................................... 22 
4.11. Visit Windows..................................................................................................... 23 
4.12. Interim Analyses ................................................................................................ 23 
5.
Study Analyses ............................................................................................................... 24
5.1. 
Patient Disposition ............................................................................................. 24 
5.2. 
Demographics and Baseline Characteristics ................................................... 24 
5.3. 
Safety Analyses ................................................................................................... 25 
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Section 
Page 
5.3.1. 
Study Drug Exposure ............................................................................ 25 
5.3.2. 
Adverse Events ..................................................................................... 25 
5.3.3. 
Laboratory Data .................................................................................... 27 
5.3.4. 
Vital Signs............................................................................................. 28 
5.3.5. 
Physical Examination ........................................................................... 28 
5.3.6. 
Electrocardiogram ................................................................................. 28 
5.3.7. 
Concomitant Medications ..................................................................... 28 
5.4. 
Efficacy Analyses ............................................................................................... 29 
5.4.1. 
Primary Efficacy Analysis .................................................................... 29 
5.4.2. 
Secondary Efficacy Analyses ............................................................... 29 
5.4.3. 
Exploratory Analyses ............................................................................ 31 
5.5. 
Pharmacokinetic Analyses ................................................................................ 32 
6. 
Changes to Planned Analyses ....................................................................................... 34 
7. 
References ....................................................................................................................... 35 
8. 
Clinical Study Report Appendices ............................................................................... 36 
8.1. 
List of Statistical Tables, Figures, and Listings to be Generated .................. 36 
8.2. 
Statistical Table and Figure Shells ................................................................... 42 
8.3. 
Data Listing Shells ............................................................................................. 97 
9. 
Revision History ........................................................................................................... 139 
10. 
Appendices .................................................................................................................... 140 
10.1. Appendix 1: Evaluation of Response to Treatment and Disease 
Status ................................................................................................................. 140 
10.2. Appendix 2: Classification of Disease Response for 
Waldenström’s Macroglobulinemia ............................................................... 142 
 
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TABLES AND FIGURES INCLUDED IN THE TEXT 
Table/Figure 
Page 
Figure 2-1 
Overall Study Design ........................................................................................... 10 
Table 2-2 
Schedule of Study Events – Screening, Day 1, End-of-Treatment 
(EOT), End-of-Study (EOS) ................................................................................ 15 
Table 2-3 
Schedule of Study Events – 8-week cycles through Week 2416 .......................... 16 
Table 2-4 
Schedule of Study Events – at second weekly dosing – Weeks 1 – 2425............. 17 
Table 2-5 
Pharmacokinetic Parameters for Analysis ........................................................... 19 
Table 10-1 
Summary of Evaluation of Response to Treatment and Disease Status ............ 140 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
ATC 
Anatomic Therapeutic Class 
BMI 
Body Mass Index 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
DRC 
Data Review Committee 
ECG 
Electrocardiogram 
EOS 
End-of-Study 
EOT 
End-of-Treatment 
ICH 
International Conference on Harmonization  
IgM 
Immunoglobulin M  
IRB 
Institutional Review Board 
ISR 
Injection Site Reaction 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Minor Response 
MTD 
Maximum Tolerated Dose 
ORR 
Objective Response Rate 
PD 
Progressive Disease 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PR 
Partial Response 
PT 
Preferred Term 
Rel Day 
Relative Study Day 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Stable Disease 
SI 
International System of Units 
TEAE 
Treatment-Emergent Adverse Event 
TLR 
Toll-Like Receptor 
VGPR 
Very Good Partial Response 
WHO 
World Health Organization 
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Abbreviation 
Definition 
WM 
Waldenström’s Macroglobulinemia 
 
 
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1.
STATISTICAL ANALYSIS PLAN OBJECTIVES
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objectives.  Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided.  The statistical 
analyses and summary tabulations described in this SAP will provide the basis for the results 
sections of the clinical study report (CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
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2.
INFORMATION FROM THE STUDY PROTOCOL
2.1. 
Introduction and Objectives
2.1.1. 
Introduction
Waldenström’s Macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder 
characterized by a lymphoplasmacytic infiltrate in the bone marrow and high levels of a 
monoclonal immunoglobulin M (IgM) in the serum (Dimopoulos et al, 2008).The disease can 
have a chronic, indolent course, with patients remaining asymptomatic for years. The principal 
complications include manifestations of the monoclonal gammopathy, including symptomatic 
hyperviscosity, cryoglobulinemia, and cold agglutinin disease; disease-related cytopenia; bulky 
adenopathy or organomegaly; severe neuropathy; amyloidosis; and disease transformation. 
Many of the agents used in refractory or relapsing WM are cytotoxic or sharply 
immunosuppressive and have substantial safety risks in elderly patients that are characteristic of 
this disease. A novel targeted agent that provided a beneficial treatment effect with a better 
tolerability profile would address an unmet need in WM. 
IMO-8400 is a second-generation oligonucleotide antagonist of Toll-like receptors (TLR) 7, 8 
and 9, which blocks immune activation mediated through those receptors. In a Phase 1 study 
IMO-8400 was administered to healthy adults by subcutaneous (SC) injection at single-doses 
and multiple-doses (once weekly for 4 weeks) up to 0.6 mg/kg (see protocol Section 5.4.1 for 
details). All treatments were well-tolerated, with mild injection site reactions and no pattern of 
systemic reactions or laboratory changes. 
In recent studies, a high frequency of mutation in the signaling pathway downstream of TLR7, 8 
and 9 has been identified in patients with B-cell malignancies, including more than 90% of 
patients with WM (Treon et al, 2012). In vitro studies of B-cell tumor lines indicate that such 
mutations are associated with an increase in cell activation, proliferation and survival (Young 
and Staudt, 2013), and that loss of endosomal TLRs results in markedly decreased cell 
proliferation and survival (Lim, Barton, and Staudt, 2013). Data from Idera indicates that 
treatment of such cell lines with IMO-8400 has a similar effect.  Further information about the 
preclinical and clinical characteristics of IMO-8400 may be found in the Investigator’s 
Brochure. 
The current study represents the first clinical trial of IMO-8400 in patients with B-cell 
malignancy. 
2.1.2. 
Study Objectives 
2.1.2.1. 
Primary Objective 
The primary objective is to evaluate the safety and tolerability of escalating dose levels of IMO-
8400 administered by SC injection in patients with relapsed or refractory WM. 
2.1.2.2. 
Secondary Objectives 
The secondary objectives are:  
•
To assess the treatment effect (clinical activity) of escalating dose levels of IMO-8400 
using disease-specific international guidelines for classifying clinical response (Owen et 
al, 2012).
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•
To identify an optimal dose of IMO-8400 for further clinical evaluation.
•
To characterize the pharmacokinetics of escalating dose levels of IMO-8400
administered by SC injection.
2.1.2.3. 
Exploratory Objectives 
The exploratory objectives are:  
•
To investigate associations between the treatment effect of IMO-8400 and selected
biomarkers (e.g., serum cytokines, MyD88 L265P mutation, levels of MyD88
expression).
•
To assess the potential immunogenicity of IMO-8400 administered by SC injection.
2.2. 
Study Design 
2.2.1. 
Synopsis of Study Design  
This is an open-label, multiple-dose, dose escalation study of IMO-8400 in patients with 
relapsed or refractory WM. The overall study design includes Part A, a dose escalation phase to 
investigate the safety and tolerability of 3 planned and 2 contingency dose levels of IMO-8400, 
and Part B, an expansion phase to further investigate the efficacy of the maximum tolerated 
dose (MTD) identified in the escalation phase (Figure 2-1).  
Figure 2-1 
Overall Study Design 
2.2.1.1. 
Part A: Dose-escalation 
2.2.1.1.1. Dose-escalation Cohorts 
The dose-escalation cohorts (3 to 6 patients each) will systematically evaluate the safety and 
tolerability of IMO-8400 at increasing dose levels in order to identify the MTD. See Protocol 
Section 9 for further details on study treatment administration.  
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•
The three planned dose levels are IMO-8400 at 0.6, 1.2, and 2.4 mg/kg/week (cohorts A1,
A2, and A3, respectively, representing two-fold escalation). Weekly exposure is based on
body weight at screening up to a maximum weekly exposure representing 125 kg equivalent.
•
Provision is made for contingency cohorts at intermediate dose levels of 0.9 or 1.8
mg/kg/week (cohorts B1 and B2, respectively) to permit dose de-escalation.
Administration of the total weekly exposure will vary by dose level to facilitate giving all doses 
by subcutaneous injection at practical dose volumes (all <0.88 mL per injection) and solution 
concentrations.  
•
For dose levels (weekly exposures) of 0.6, 0.9, and 1.2 mg/kg, the total weekly exposure
will be given as a single once weekly SC injection.
•
To achieve higher weekly exposures (1.8 and 2.4 mg/kg/week), the total dose will be
divided into two equal portions administered as separate subcutaneous injections (each 0.9
or 1.2 mg/kg per injection, respectively) over the course of the week, preferably 72 to 96
hours apart (minimum 48 hours).
2.2.1.1.2. Dose-escalation Procedures 
Procedures for patient safety during dose-escalation are summarized below and presented in 
detail in the protocol sections and sections of this document indicated: 
•
Explicit definitions for identifying suspected adverse reactions as dose-limiting toxicity 
(DLT) events (see Section 2.2.5.1.1).
•
Clinical or laboratory events classified Grade 3 or higher by the National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03.
•
Explicit definition for MTD (see Section 2.2.5.1.1).
•
All injections of study medication will be administered by study personnel and all patients
observed for 2 hours following the first injection and for at least 30 min following all other
injections.
•
Detailed provisions for management of study drug in individual patients based on safety,
tolerability, and disease response (see Section 2.2.2.1 and Protocol Section 7.5).
•
Constitution of a Data Review Committee (DRC) to make recommendations for 
dose-escalation and determination of the MTD (see Sections 2.2.3 and 2.2.5.1.1)
2.2.1.1.3. Dose-escalation Enrollment and Review 
Each dose-escalation cohort is expected to enroll at least 3 patients, with a maximum of 6. 
•
If the initial 3 patients all complete 4 weeks of treatment without a DLT event, the DRC will
conduct a dose-escalation review.
•
If 1of the initial 3 patients experiences a DLT event prior to completing 4 weeks of
treatment, then enrollment at that dose level will continue to a total of 6 patients and the
dose-escalation review will be done when all 6 patients have completed 4 weeks treatment.
•
If 2 patients at a dose-level experience DLT events during the first 4weeks of treatment, then
no further patients will be enrolled until the DRC completes a review, which should be done
as soon as feasible.
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The DRC review will include all safety data available for the cohort. The following represent 
anticipated outcomes for the review process. 
•
Approve enrollment in the expansion cohort at that dose level, if applicable (See Section
2.2.1.2) 
•
Dose escalation – progression to the next planned dose level.
•
Continue cohort enrollment (applicable only to review after three patients) – enroll up to six
patients at the current dose level to obtain additional safety data for subsequent review.
•
Dose de-escalation – enrollment of an intermediate level contingency cohort (see 
Figure 2-1) to facilitate identifying the MTD (see Section 2.2.5.1.1).
•
No further dose escalation enrollment – at this time the DRC will indicate the dose level
they consider represents the MTD.
2.2.1.2. 
Part B: Dose Expansion 
2.2.1.2.1. Expansion Cohorts 
The expansion cohorts provide for additional enrollment at each of 2 dose levels to assess the 
dose dependence of clinical response. A maximum of 9 patients may be enrolled at each 
specified dose level, that is, no more than 9 patients total in (a) the dose escalation cohort at that 
level plus (b) the corresponding expansion cohort. 
•
Cohort M1, 0.6 mg/kg/week
•
Expansion at this dose level will proceed only after the DRC reviews dose escalation
cohort A1 (0.6 mg/kg) and concurs.
•
Patients may be enrolled in Cohort M1 while other dose escalation cohorts are
proceeding. If both Cohort M1 and a dose escalation cohort are available for enrollment
concurrently, the Sponsor may determine which cohort has priority.
•
Cohort M2, at MTD as defined by the dose escalation process
•
Enrollment in this cohort will proceed only after the DRC either (a) determines the MTD
or (b) concurs with further enrollment at 2.4 mg/kg/week, the maximum dose level under
this protocol.
2.2.2. 
Stopping Rules  
The sponsor reserves the right to discontinue the study for safety or administrative reasons at 
any time. Should the study be terminated and/or the site closed for whatever reason, all 
documentation and study medication pertaining to the study must be returned to the sponsor or 
its representative. 
If the trial is terminated prematurely or suspended, the Sponsor will promptly inform the 
participating Investigators and institutions, the regulatory authorities, and the Institutional 
Review Board (IRB) of the termination or suspension and the reason(s) for the action. 
The maximum exposures to IMO-8400, the investigational agent in this study, will be as 
follows: 
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•
Maximum number of patients: 24 patients in planned escalation and expansion cohorts;
potential for additional patients in contingency cohorts or as replacements
•
Maximum dose level: 2.4 mg/kg/wk (two doses of 1.2 mg/kg each week)
•
Maximum treatment duration: 24 weeks
2.2.2.1. 
Stopping Rules for Individual Patients 
Each enrolled patient will receive IMO-8400 at the assigned dose level until the earliest of: 
•
DLT event – see Section 2.2.5.1.1
•
Disease progression – based on assessments at Weeks 9 and 17, or as prompted by new 
signs, symptoms, and laboratory findings, and classified according to international 
guidelines (Owen et al, 2012) (see Sections 10.1 and 10.2 for details)
•
Completion of 24 weeks treatment – Provision is made for extended treatment under a
separate protocol (8400-404) at the request of the Investigator (see Protocol Section 7.5.4).
Study treatment will be discontinued for DLT clinical events and for disease progression. For 
DLT laboratory events, provision is made for pausing treatment for up to three weeks and, if the 
acute toxicity improves sufficiently, resuming treatment at a lower dose level (see Protocol 
Section 7.5.2 for details). 
2.2.3. 
Data Review Committee (DRC) 
Members of the DRC will have appropriate experience treating patients with hematologic 
malignancies and/or conducting early phase trials of investigational drugs and will include the 
following: 
•
An independent physician not otherwise involved with the study.
•
The medical monitor for the study.
•
A participating Investigator.
•
A physician representative of the Sponsor.
The roles of the DRC are to: 
•
Review and provide definitive adjudication on individual DLTs (see Section 2.2.5.1.1).
•
Perform dose-escalation review and make specific recommendations for the progress of the
study (see Section 2.2.1.1.3).
•
Determine the MTD (see Section 2.2.5.1.1).
A patient will be considered evaluable for purposes of DRC review if they meet either of the 
following criteria: 
•
Received at least one (1) dose of study drug and had treatment discontinued because of a
DLT event as defined in Protocol Section 7.3.1; or
•
Received four (4) doses of study drug and completed Week 5 assessment procedures.
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2.2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 2-2, 
Table 2-3, and Table 2-4. 
The schedule is presented relative to the day and time of dosing. All Days are relative to the 
day of the first injection of study drug, designated Day 1. All weeks are relative to Week 1, 
defined as Day 1 through Day 7, inclusive. All times are relative to injection, designated 0 hr; 
“pre-dose” vital signs are to occur within 1 hour prior to injection; all other pre-dose procedures 
are to occur prior to injection on the same calendar day. 
The screening evaluation may be performed up to 21 days prior to dosing. 
Clinical and laboratory assessments for disease status will be conducted at screening, at Weeks 
9 and 17 during study treatment, at the end-of-treatment (EOT) visit (week 25), and at the end-
of-study (EOS) visit (week 29). Radiologic imaging and bone marrow biopsy will be performed 
at screening and at EOT visit. Disease status will be classified using disease-specific criteria as 
proposed by the VIth International Workshop on Waldenström’s Macroglobulinemia (Owen et 
al, 2012) (see Sections 10.1 and 10.2). 
In this study the duration of treatment is up to 24 weeks.  This duration is consistent with the 
patterns of early treatment termination in the event of toxicity or disease progression with 
administration of investigational drugs in patients with advanced malignancies. Provision is 
made for extension of treatment under a separate protocol (see Protocol Section 7.5.4). 
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Table 2-2 
Schedule of Study Events – Screening, Day 1, End-of-Treatment (EOT), 
End-of-Study (EOS) 
Event 
Visit1 
Screen2 
Day 1 
 
EOT 
EOS 
 
Week 
 
 
1 
 
 
253 
293 
 
Hour 
 
pre 
0 h 
post 
 
 
 
Informed Consent4 
X 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
X 
X 
Body weight 
X5 
X 
 
 
 
X 
X 
Vital signs6 
X 
X 
 
X7 
 
X 
X 
Assessment of Tumor Status8 
X 
 
 
 
 
X 
X 
ECOG 
X 
 
 
 
 
X 
X 
CT or MRI imaging9 
X 
 
 
 
 
X 
 
Safety Laboratory Tests10 
X 
X 
 
 
 
X 
X 
Urinalysis 
X 
X 
 
 
 
X 
X 
12-lead ECG 
X 
X 
 
 
 
X 
X 
Pregnancy test (females only)11 
X 
 
 
 
 
X 
X 
Serology 
X 
 
 
 
 
 
 
Pharmacokinetics 
 
X 
 
X13 
 
X 
X 
Investigational Studies14 
X 
X 
 
 
 
X 
X 
Bone Marrow Biopsy14 
X 
 
 
 
 
X 
 
Assessment of Injection Site(s)15 
 
X 
 
 
 
X 
X 
Study Drug Administration 
 
 
X 
 
 
 
 
 
AE & Concomitant Med 
Monitoring 
------From Screening to End of Study Visit --------- 
 
1 All Days are relative to the day of the first injection of study drug, designated Day 1. All weeks are relative to 
Week 1, defined as Day 1 through Day 7, inclusive. All times are relative to injection, designated 0 hr; “pre-dose” 
vital signs are to occur within 1 hour prior to injection; all other pre-dose procedures are to occur prior to injection 
on the same calendar day. 
2 Screening procedures may be performed up to 21 days prior to Day 1. 
3 If treatment is terminated prematurely for any reason, the EOT visit will be performed within 5 days of the 
decision to terminate; the EOS visit will be performed 30 to 35 days after the last dose of study drug. 
4 Informed consent must be signed prior to all study-specific screening procedures. 
5 At screening also height. 
6 Vital signs comprise heart rate, blood pressure, respiratory rate and temperature. 
7 On Day 1, post-dosing vital signs are obtained at 30 (±5) min and 2hr (±20min) after dosing. 
8 Assessment of tumor status includes clinical evaluation, serum and urine levels of monoclonal protein, serum 
viscosity, and β2-microglobulin; see Protocol Section 10.4 for details. 
9 CT or MRI imaging of chest, abdomen and pelvis with the same modality used for every assessment; see Section 
10.4 for details. 
10 Safety laboratory tests comprise hematology, chemistry and coagulation (see Protocol Section 10.7.1 for details). 
11 Serum pregnancy testing will be done at the central laboratory. 
13 At first weekly dose on Day 1, post-dose PK samples will be obtained at 1 hr (±5 min), 2 hrs (±10 min) and 4 hrs 
(±15 min). 
14 Bone Marrow Biopsy and investigational studies will be submitted to central laboratory (see Protocol Section 
10.9). 
15 Assessment of all prior injection site(s) with grading and measurement of any reaction (see Protocol Section 
11.4.4.2). In addition, on dosing days, the planned injection site will be assessed to confirm it is appropriate for use. 
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Table 2-3 
Schedule of Study Events – 8-week cycles through Week 2416 
Event 
Cycle 1, Week # 
 
2-4 
5 
6-8 
Cycle 2, Week #  
 
9 
 
10-12 
 
13 
 
14-16 
 
 Cycle 3, Week # 
 
17 
 
18-20 
 
21 
 
22-24 
 
Hour 
pre 
0 h 
post 
pre 
0 h 
post 
pre 
0 h 
post 
pre 
0 h 
post 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
217 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs18 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Assessment of Tumor Status19 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI imaging 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Laboratory Tests20 
X 
 
 
Odd 
 
 
X 
 
 
Odd 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
X 
 
 
 
 
 
Pregnancy test (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
Serology 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics21 
 
 
 
 
 
 
5,13 
 
5,13 
 
 
 
Investigational Studies22 
 
 
 
 
 
 
5,13 
 
 
 
 
 
Bone Marrow Biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Injection Site(s)23  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Study Drug Administration24 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
AE & Concomitant Med Monitoring 
---- From Screening to End of Study Visit ---- 
 
16 All Days are relative to the day of the first injection of study drug, designated Day 1. All weeks are relative to 
Week 1, defined as Day 1 through Day 7, inclusive. All times are relative to injection, designated 0 hr; “pre-dose” 
vital signs are to occur within 1 hour prior to injection; all other pre-dose procedures are to occur prior to injection 
on the same calendar day.  
17 Physical examination will be done on Week 2 of Cycle 1. 
18 Vital signs comprise heart rate, blood pressure, respiratory rate and temperature. Post-dose vital signs are 
obtained at 0.5 hour after dosing. 
19 Assessment of tumor status includes clinical evaluation, serum and urine levels of monoclonal protein, serum 
viscosity, and β2-microglobulin; see Protocol Section 10.4 for details. Samples will be collected for total and 
monoclonal serum IgM at Week 23 (other tumor assessments not required at Week 23). 
20 The full panel of safety laboratory tests (hematology, chemistry and coagulation) will be done on Weeks 5, 9, 13, 
17, and 21; a focused panel (hematology, selected chemistry) will be done on Weeks 3, 7, 11, 15, 19, and 23; see 
Protocol Section 10.7.1 for details). 
21 PK samples will be collected on day of dosing at the first weekly dose on Weeks 5 and 13 as shown. Post-dose 
PK samples will be obtained at 1 hr (±5 min), 2 hrs (±10 min) and 4 hrs (±15 min) after dosing.  
22 Investigational studies will be collected pre-dose at Weeks 5 and 13 (see Protocol Section 10.9 for details). 
23 Assessment of all prior injection site(s) with grading and measurement of any reaction (see Section 11.4.4.2). In 
addition, on dosing days, the planned injection site will be assessed to confirm it is appropriate for use. 
24 Schedule applies to all patients receiving once weekly dosing and to the first weekly dose for all patients 
receiving twice weekly dosing (see Protocol Sections 2.3.2 and 9.4 for details).  
 
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Table 2-4 
Schedule of Study Events – at second weekly dosing – Weeks 1 – 2425 
Event 
All Weeks 
Second Weekly Dose 
 
Hour 
pre 
0 h 
post 
Vital Signs26 
X 
 
X 
Assessment of Injection Site27 
X 
 
 
Study Drug Administration 
 
X 
 
 
25 Schedule applies to all patients receiving twice weekly dosing. The dosing interval between the successive doses 
on the twice weekly schedule doses is expected to be 3 or 4 days (approximately 72 to 96 hrs), but no less than 2 
days (~48 hrs) (see Protocol Sections 2.3.3and 9.4 for details). All times are relative to injection, designated 0 hr; 
“pre-dose” vital signs are to occur within 1 hour prior to injection; all other pre-dose procedures are to occur prior 
to injection on the same calendar day.  
26 Vital signs comprise heart rate, blood pressure, respiratory rate and temperature. Post-dose vital signs are 
obtained at 30 min (± 5 min) after dosing.  
27 Assessment of all prior injection site(s) with grading and measurement of any reaction (see Protocol Section 
11.4.4.2). In addition, on dosing days, the planned injection site will be assessed to confirm it is appropriate for use.  
 
 
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2.2.5. 
Safety, Efficacy, and Pharmacokinetic Parameters 
2.2.5.1. 
Safety Parameters 
The safety and tolerability of IMO-8400 will be assessed using reported and observed adverse 
events (AEs) as well as scheduled safety observations including vital signs, physical 
examination, laboratory tests (hematology, chemistry, and coagulation), urinalysis, and 
electrocardiograms (ECGs). 
Adverse Events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 16.0 and tabulated by event, grade, and relationship to study therapy. Laboratory results, 
vital signs, and ECG parameters will be summarized using descriptive statistics. Laboratory 
values will also be graded according to NCI CTCAE, Version 4.03, and summarized using shift 
tables. 
2.2.5.1.1. Definition of Dose Limiting Toxicity and Maximum Tolerated Dose  
A DLT can be either a clinical or laboratory AE. A potential DLT event is defined as a 
treatment-emergent (i.e. onset after first injection of study drug) AE that meets either of the 
following criteria using NCI CTCAE v4.03 grading:  
• Is a clinical event of Grade 3 or higher severity. 
• Is a confirmed laboratory finding of Grade 3 or higher severity. 
The DRC will review all potential DLT events to assess causality, i.e., relationship to study drug 
(related, possible related, unlikely related, or not related). Events will be considered DLT events 
unless they are unanimously assessed as “Not related”, that is, a factor other than study drug is 
the cause of the event.  
The MTD is the dose level meeting both of the following criteria: 
• It is below the level at which 2 or more patients experienced DLTs during the first four 
weeks of treatment; 
• It is a dose level at which no more than 1 patient experienced DLTs during the first four 
weeks of treatment. 
 
2.2.5.2. 
Efficacy Parameters 
The primary treatment effect parameter is objective response rate (ORR), defined as the 
occurrence of complete response (CR), very good partial response (VGPR), partial response 
(PR), or minimal response (MR), presented by dose level and overall.  
Secondary efficacy endpoints include: 
• The distribution of response classes identified by best overall response.  
• Duration of response (DOR) – Time from the first occurrence of objective response (CR, 
VGPR, PR, or MR) to the first documented evidence of disease progression. 
• Time to progression (TTP) – Time from the initiation of treatment to disease progression 
with deaths due to unrelated causes censored. 
• Progression-free survival (PFS) – Time from the initiation of treatment to disease 
progression or death from any cause. 
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• Time to best observed response – Time from the initiation of treatment to best observed 
category of response 
• Percent and absolute change in quantitative serum levels of monoclonal IgM. 
• Percent and absolute change in hematology values (if abnormal at baseline). 
Exploratory endpoints include the following investigational factors, analyzed with regard to 
disease status: 
• Presence or absence of MyD88 L265P mutation in tumor cells. 
• Serum cytokine levels. 
• Serum levels of antibody to IMO-8400. 
Additional exploratory analysis may be performed on additional endpoints of interest or 
subpopulations. 
2.2.5.3. 
Pharmacokinetic Parameters 
Blood samples for plasma levels of IMO-8400 will be collected as scheduled. Samples will be 
analyzed for IMO-8400 concentration using a ligand binding (hybridization) bioanalytical 
method (estimated sensitivity, 20 ng/mL). Pharmacokinetic data will be analyzed using standard 
non-compartmental methods. 
The pharmacokinetic variables to be determined and the time points of determination are 
summarized below: 
Table 2-5 
Pharmacokinetic Parameters for Analysis 
Parameter 
Description 
Equation 
AUC0-last 
Area-under-the-curve from 0 to last measurable 
concentration 
 
Cmax 
Maximum plasma concentration; the highest 
concentration observed during a dosage interval. 
 
Tmax 
The time Cmax was observed. 
 
RA 
Accumulation Ratio: Ratio of drug concentrations 
observed during a dosing interval at steady-state 
divided by drug concentrations seen during the 
dosing interval after a single (first) dose 
AUC0-last - multiple dose /  
AUC0-last - single (first) dose 
 
 
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3. 
SUBJECT POPULATION 
3.1. 
Population Definitions 
The following subject populations will be evaluated and used for presentation and analysis of 
the data: 
Intent-to-Treat (ITT)/Safety Population:  All patients who received at least one dose of study 
treatment. 
Per Protocol (PP) Population: All patients who have one or more scheduled post-treatment 
tumor assessments and no major protocol deviations.  
Pharmacokinetic (PK) Population: All patients with sufficient data to determine PK parameters. 
The primary efficacy endpoint (objective response rate) will be analyzed for both ITT/Safety 
and PP populations. Secondary and exploratory efficacy endpoints will be analyzed using only 
PP population, with the exception of several key secondary efficacy endpoints, which will be 
analyzed for the ITT/Safety population as well.   
The ITT/Safety population is the primary population for the analysis of safety parameters. The 
PK population is the primary population for the analysis of PK parameters.   
3.2. 
Protocol Deviations 
For protocol deviations relating to individual patients, the event and relevant circumstances will 
be recorded on source documents and on the appropriate eCRF. Protocol deviations will be 
determined and documented prior to database lock.  Upon assessment of protocol deviations, the 
Sponsor may determine to remove a patient’s data from the PP population in an effort to 
maintain full compliance with study procedures.   
All protocol deviations will be presented in a data listing. 
 
Relevant Output 
Listing 16.2.3  
Protocol Deviations 
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4.
GENERAL STATISTICAL METHODS
4.1. 
Sample Size Justification
Consistent with the primary objective, the study design represents a pragmatic assessment of 
safety and tolerability across different dose levels of IMO-8400 based upon clinical evaluations 
and laboratory tests. 
It is anticipated that there will be sufficient patients to permit a preliminary evaluation of 
treatment effect at the expansion dose levels (see Section 2.2.1.2) and globally across dose 
levels. 
A power calculation relating to the primary treatment effect analysis was performed using the 
following assumptions: 
•
9 patients at an expansion dose level or 18 patients across the two expansion dose levels.
•
True response rate at least 50%.
•
Using a one-sided exact test and significance level α = 0.025.
•
A hypothetical response rate of 10%.
Under these assumptions, 9 patients will provide at least 74% power for rejecting the 
hypothetical response rate; and 18 patients will provide at least 96% power. 
4.2. 
General Methods 
All data listings that contain an evaluation date will contain a relative study day (Rel Day).  For 
the purpose of analysis, study days will be designated as follows:  
•
Day 1 is defined as the calendar day of the first injection of study drug.
•
The days prior to Day 1 are designated Day –1, Day –2, etc; there is no Day 0.
•
The days following the day of the first injection of study drug are designated Day 2, Day 3,
etc.
•
The day of the last injection of study drug is indicated by adding the suffix "L", e.g., if the
last injection is administered on Day 43, it will be displayed as "Day 43L".
•
The days following the last injection of study drug are designated Day 1P, Day 2P, etc.
•
The times of events related to dosing of study drug will be designated as minutes or hours
before or after the time of dosing (i.e., the subcutaneous injection of study drug), which is
designated as t = 0 (zero). Thus, 15 minutes prior to dosing is t = –15 min; 2 hour after
dosing is designated t = 2 h.
All output will be incorporated into Microsoft Word files, sorted and labeled according to the 
International Conference on Harmonisation (ICH) recommendations, and formatted to the 
appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, PK, and safety 
parameters.  For categorical variables, summary tabulations of the number and percentage of 
patients within each category (with a category for missing data) of the parameter will be 
presented.  For continuous variables, the number of patients, mean, median, standard deviation, 
minimum, and maximum values will be presented. For some efficacy parameters, a confidence 
interval will also be presented, as described in more detail in Section 5.  
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Data will be presented by subject and summarized by dose and overall, including a pooled 
cohort of all IMO-8400 dosed groups. All data will be included in summary tabulations..   
4.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.3 
or above, unless otherwise noted.  Adverse events will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) Version 16.0 (or later).  Concomitant medications will be 
coded using the World Health Organization (WHO) Drug Dictionary Version Q12013 (or later). 
4.4. 
Baseline Definitions 
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug. 
4.5. 
Methods of Pooling Data 
Data will be pooled across all study sites. All IMO-8400 dosed subjects will be pooled together 
and presented separately by dose level. 
4.6. 
Adjustments for Covariates 
In an exploratory efficacy analysis for all efficacy endpoints, the presence or absence of the 
MyD88 L265P mutation may be included in the model as a covariate. 
4.7. 
Multiple Comparisons 
No adjustments for multiple comparisons will be made.  As the primary purpose of this study is 
to assess the safety and tolerability of IMO-8400, efficacy assessments are secondary and the 
type I error rate will not be adjusted. 
4.8. 
Subpopulations 
In an exploratory efficacy analysis, all efficacy endpoints will be repeated by MyD88 L265P 
mutation status subpopulation (i.e., those with and without the mutation as measured at 
baseline).  
4.9. 
Withdrawals, Dropouts, Loss to Follow-up 
A patient who does not meet the criteria for “evaluable” as explained above in Section 2.2.3 
may be replaced to assure the requirements for completing the cohort are met. Replacement 
patients will be identified by distinctive patient numbers and will receive the same dose level as 
the patient being replaced. 
4.10. 
Missing, Unused, and Spurious Data 
Missing data will not be imputed. All the data recorded on the case report form (CRF) will be 
included in data listings that will accompany the CSR. 
When tabulating AE data, partial dates will be handled as follows.  If the day of the month is 
missing, the onset day will be set to the first day of the month unless it is the same month and 
year as study treatment.  In this case, in order to conservatively report the event as treatment-
emergent, the onset date will be assumed to be the first date of treatment.  If the onset day and 
month are both missing, the day and month will be assumed to be January 1, unless the event 
occurred in the same year as the study treatment.  In this case, the event onset will be coded to 
the day of treatment in order to conservatively report the event as treatment-emergent.  A 
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missing onset date will be coded as the first day of treatment. Listings will present all data as 
reported (i.e., without imputations). 
4.11. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule; visits outside of this 
schedule will be listed as a protocol deviation.  Visits occuring outside of the visit windows as 
described in the protocol schedule will be included in summary tabulations if corresponding to a 
scheduled visit. Unscheduled assessments will not be summarized in tabulations that present 
data by visit.  However, in shift tables or summaries of best response, data from unscheduled 
assessments will be included.  Any data from unscheduled assessments will be listed. 
In data listings, the relative day of all dates will be presented.  
4.12. 
Interim Analyses 
Interim safety data will be examined on an ongoing basis to ensure patient safety and to comply 
with the clinical trial dose escalation rules. There is no formal interim analysis planned for 
efficacy.  
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5. 
STUDY ANALYSES 
5.1. 
Patient Disposition 
Patient disposition will be tabulated and will include the number screened, the number screen 
failed, the number enrolled, the number treated at each dose level, the number prematurely 
discontinued from treatment, the reason for discontinuation, and the number in each subject 
population for analysis. The definitions of the parameters used in the disposition table are given 
below. 
Screened: Patients who signed consent and underwent screening procedure. 
Screen Failure: Screened patients deemed ineligible to enroll in the study due to failure to meet 
the inclusion/exclusion criteria. 
Enrolled: Patients who received at least 1 dose of study medication. 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal and premature treatment discontinuation will be presented. A by-patient data 
listing of inclusion/exclusion criteria not met and will also be presented. 
Relevant Output 
Table 14.1.1.1  
Patient Enrollment and Disposition 
Listing 16.2.1.1 
Patients Discontinuing Treatment Prematurely  
Listing 16.2.1.2 
End of Treatment (EOT) Visit Status  
Listing 16.2.1.3 
End of Study (EOS) Visit Status  
Listing 16.2.2.1 
Inclusion Criteria  
Listing 16.2.2.2 
Exclusion Criteria 
Listing 16.2.2.3 
Listing of Inclusion/Exclusion Criteria Not Met 
Listing 16.2.2.4 
Intent–To-Treat Patients Excluded from Per-Protocol Population 
  
5.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics, including medical and disease history, will be 
summarized and presented by dose level and overall.  Age, height, weight, body mass index 
(BMI), and baseline ECOG Score will be summarized using descriptive statistics (number of 
patients, mean, standard deviation, median, minimum, and maximum).  The number and 
percentage of patients in each ethnicity, race and gender category will also be presented.  
Disease history will include number and percentage of subjects with presence or absence of 
MyD88 L265P mutation in tumor cells, whether at least one treatment related AE has been 
recorded in the past 3 months, and whether the subject has been hospitalized in the past year.  
Time since WM diagnosis, time since first treatment for WM, and time since most recent 
hospitalization will be summarized using descriptive statistics. 
Prior treatments will include number and percentage of patients who have received at least one 
prior therapy, including type of treatment and best overall response.  
Demographic, baseline, and medical history data for each subject will be provided in data 
listings. 
 
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Relevant Output 
Table 14.1.2.1 
Demographic Characteristics (ITT/Safety Population) 
Tabel 14.1.2.2 
Baseline Characteristics (ITT/Safety Population) 
Table 14.1.3.1   
Disease History (ITT/Safety Population) 
 
Table 14.1.4.1   
Prior Treatments (ITT/Safety Population) 
Listing 16.2.4.1   
Demographic Characteristics  
Listing 16.2.4.2   
Medical History 
 
 
Listing 16.2.4.3A   Waldenström’s Macroglobulinemia Disease History – Part 1 
Listing 16.2.4.3B 
Waldenström’s Macroglobulinemia Disease History – Part 2 
Listing 16.2.4.4   
Prior Waldenström’s Macroglobulinemia Therapy 
 
Listing 16.2.8.6  
Urine Pregnancy Test Results 
Listing 16.2.9.3 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
5.3. 
Safety Analyses 
Safety analyses will be conducted using the Safety population. Safety observations will be 
analyzed using descriptive statistics and tabulation. No formal statistical comparisons are 
planned. All safety data will be presented in listings. 
5.3.1. 
Study Drug Exposure 
Study drug exposure will be tabulated by the number of cycles of study drug received. The 
number and percentage of patients will be reported by dose group and overall. Cumulative dose 
(mg) will also be summarized by dose group and overall, where cumulative dose is the dose 
injected multiplied times the number of injections, taking into account any intrapatient dose 
adjustments. The number of missed doses will also be tabulated, as well as the reason the dose 
was missed. Dosing information for each subject will be presented in a data listing.  
Relevant Output 
Table 14.3.5.1   
Study Drug Exposure (ITT/ Safety Population) 
Table 14.3.5.2 
Study Drug Exposure (PP Population) 
Listing 16.2.5.1  
Study Drug Exposure 
 
 
5.3.2. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system and displayed in tables and 
data listings using system organ class (SOC) and preferred term. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as:  
− any AE with onset after the first administration of study medication (Day 1) through the 
EOS visit,  
− any AE that was present at baseline but worsened in intensity or was subsequently 
considered drug-related by the Investigator through the EOS visit, or 
− any AE with missing onset date.  
The incidence of AEs will be presented by individual and pooled dose levels.  For each 
tabulation, AEs are summarized by subject incidence rates; therefore, in any tabulation, a 
subject contributes only once to the count for a given AE (SOC or preferred term), irrespective 
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of the number of episodes of a particular AE term reported.  No formal hypothesis-testing 
analysis of AE incidence rates will be performed. 
The number and percentage of patients with any AE, injection site reaction (ISR), treatment-
emergent AE (TEAE), TEAE related to study drug, grade ≥3 TEAE, serious AE (SAE) and 
DLT AE will be presented.   
Additional summary tables by SOC and preferred term will be produced for the following:  
• All TEAEs 
• All TEAEs by relationship to study drug (drug-related, not drug-related) where drug-related 
AEs include events with probable, possible and missing relationships 
• All non-serious TEAEs 
• All TEAEs by severity grade (grade 1 or 2, grade ≥3) 
• All DLTs 
For each injection site, local ISRs will be summarized by the worst grade post-treatment for 
each symptom.  Pain, tenderness, pruritus and induration will be summarized using number and 
percentage of patients by toxicity grade. Blisters, ulceration and necrosis measurements (mm) 
will be summarized descriptively, including quartiles and 90th percentiles, as well as 
categorically by grade.  For each injection site the worst grade post treatment is counted per 
subject and symptom. In addition, each symptom will be summarized over time by visit and 
grade.  
All AEs occurring on-study will be listed in subject data listings. Additionally, a glossary of AE 
verbatim terms by preferred term and SOC will be provided.   A separate listing for system 
organ class complete name and their corresponding abbreviations will be provided.  
By-subject listings will also be provided for the following:  subject deaths, SAEs, and AEs 
leading to withdrawal. 
Relevant Output 
Table 14.3.1.1 
Summary of Adverse Events (ITT/ Safety Population) 
Table 14.3.1.2 
Incidence of Treatment-Emergent Adverse Events by MedDRA System Organ Class 
and Preferred Term (ITT/ Safety Population) 
Table 14.3.1.3 
Incidence of Treatment-Emergent Adverse Events by Relationship to Study Drug and 
by MedDRA System Organ Class and Preferred Term (ITT/ Safety Population) 
Table 14.3.1.4 
Incidence of Non-Serious Adverse Events, by MedDRA System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.5 
Incidence of Treatment-Emergent Adverse Events by Intensity and by MedDRA 
System Organ Class and Preferred Term (ITT/ Safety Population) 
Table 14.3.1.6 
Incidence of Dose-Limiting Toxicity Adverse Events by MedDRA System Organ 
Class and Preferred Term (ITT/ Safety Population) 
Table 14.3.1.7 
Incidence of Local Injection Site Reactions Worst Grade Post Baseline (ITT/ Safety 
Population) 
Table 14.3.1.8 
Incidence of Local Injection Site Reactions Worst Grade by Visit (ITT/ Safety 
Population) 
Table 14.3.2.1   
Listing of Deaths 
Table 14.3.2.2   
Listing of Serious Adverse Events  
Table 14.3.2.3   
Listing of Treatment Discontinuations Due to Adverse Events 
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Listing 16.0.1 
System Organ Class Abbreviations 
Listing 16.2.7.1   Adverse Events by Patient and System Organ Class / Preferred Term  
Listing 16.2.7.2 
Adverse Events by System Organ Class / Preferred Term  
Listing 16.2.7.3 
Glossary of Adverse Event Verbatim Terms by MedDRA System Organ Class, 
Preferred Term, and Patient 
Listing 16.2.7.4 
Injection Site Reaction Assessments 
Listing 16.2.7.5 
Patient Reported Injection Site Reactions  
Listing 16.2.7.6 
Observed Injection Site Reactions  
5.3.3. 
Laboratory Data 
Clinical laboratory values will be reported in US units. 
This study collects central laboratory data, but local laboratory data may be collected for the 
screening visit.  Local laboratory data will not be summarized but it will be included in the 
laboratory listings.   
The actual value and change from baseline to each on-study evaluation will be summarized for 
hematology, chemistry and coagulation parameters.   A boxplot figure representing each lab 
parameter over time will be presented for hematology, chemistry and coagulation parameters by 
dose level and overall.  
Laboratory CTCAE grades shift from baseline to the worst grade post baseline will be tabulated 
for individual and pooled dose groups using number and percentage of patients.  These 
comparisons will include values from unscheduled visits. 
All laboratory data will be provided in data listings.  A separate listing including normal ranges 
for all hematology, chemistry, coagulation and urinalysis parameters will be provided. 
A subset listing will be presented for all clinically significant and abnormal laboratory values.   
Relevant Output: 
Table 14.3.4.1   
Listing of Clinically Significant Abnormal Laboratory Values (ITT/ Safety 
Population) 
Table 14.3.5.3 
Summary and Change from Baseline for Hematology Parameters by Time Point and 
Dose Group (ITT/ Safety Population) 
 
Figure 14.3.5.3 
Summary and Change from Baseline for Hematology Parameters by Time Point and 
Dose Group - Box Plot (ITT/ Safety Population)  
Table 14.3.5.4 
Summary and Change from Baseline for Chemistry Parameters by Time Point and 
Dose Group (ITT/ Safety Population)  
 
Figure 14.3.5.4 
Summary and Change from Baseline for Chemistry Parameters by Time Point and 
Dose Group - Box Plot (ITT/ Safety Population)  
Table 14.3.5.5 
Summary and Change from Baseline for Coagulation Parameters by Time Point and 
Dose Group (ITT/ Safety Population)  
 
Figure 14.3.5.5 
Summary and Change from Baseline for Coagulation Parameters by Time Point and 
Dose Group - Box Plot (ITT/ Safety Population)  
Table 14.3.5.6A 
Shifts from Baseline to Worst CTC Grade Post-Baseline in Hematology Parameters 
by Dose Group (ITT/ Safety Population)  
Table 14.3.5.6B 
Shifts from Baseline to Worst CTC Grade Post-Baseline in Chemistry Parameters by 
Dose Group (ITT/ Safety Population)  
Table 14.3.5.6C 
Shifts from Baseline to Worst CTC Grade Post-Baseline in Coagulation Parameters 
by Dose Group (ITT/ Safety Population)  
 
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Listing 16.2.8.1A   Laboratory Results: Hematology – Part 1 
 
Listing 16.2.8.1B   Laboratory Results: Hematology – Part 2 
Listing 16.2.8.2   
Laboratory Results: Chemistry 
 
Listing 16.2.8.3   
Laboratory Results: Urinalysis 
 
Listing 16.2.8.4   
Laboratory Results:  Coagulation 
 
5.3.4. 
Vital Signs  
The actual value and change from baseline to each on-study evaluation will be summarized for 
vital signs, including heart rate, blood pressure, respiratory rate, and temperature. A boxplot 
figure representing each vital sign over time will be presented by dose group and overall.  
Vital sign measurements will be presented in a data listing. 
Relevant Output: 
Table 14.3.5.7   
Summary and Change from Baseline for Vital Signs by Time Point and Dose Group 
(ITT/Safety Population) 
Figure 14.3.5.7 
Summary and Change from Baseline for Vital Signs by Time Point and Dose Group 
- Box Plot (ITT/Safety Population) 
Listing 16.2.9.1  
Vital Signs  
 
5.3.5. 
Physical Examination 
All physical examination findings will be presented in a data listing. 
Relevant Output: 
Listing 16.2.9.2  
Physical Examination Findings 
 
5.3.6. 
Electrocardiogram 
Actual ECG values and change from baseline will be summarized descriptively by time point, 
including heart rate and PR, QRS, QT, and QTcF (calculated by the Fridericia correction 
formula). 
Electrocardiogram data will be provided in a data listing. 
Relevant Output: 
Table 14.3.5.8   
Summary and Change from Baseline for Electrocardiogram Results by Time Point 
and Dose Group (ITT/Safety Population) 
Table 14.3.5.9 
Listing of Abnormal Electrocardiogram Assessments (ITT/Safety Population) 
Listing 16.2.9.4   
12-Lead Electrocardiogram Interval and Overall Assessment 
Listing 16.2.9.5 
12-Lead Electrocardiogram – Comments on Abnormal Assessments  
5.3.7. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary.  Results will be 
tabulated by anatomic therapeutic class (ATC) and preferred term. 
Any medications that did not end prior to first dose will be classified as a concomitant 
medication, as well as medications that are ongoing or those missing the end date.  In case of 
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repeated occurrences per subject, a medication will only be counted once per ATC/preferred 
term. 
The use of concomitant medications will be included in a by-subject data listing. 
Relevant Output: 
Table 14.3.5.10 
Concomitant Medications (Safety Population) 
Listing 16.2.9.6   
Concomitant Medications 
5.4. 
Efficacy Analyses 
Study populations for the primary, secondary and supplemental efficacy analysis are defined in 
Section 3.1.  The primary efficacy endpoint will be analyzed for both ITT and PP populations. 
Secondary and exploratory efficacy endpoints will be analyzed using only ITT population, 
unless the difference in number of patients between ITT and PP populations is >2, in which case 
the analyses will be performed using both ITT and PP populations.   
For patients who discontinue study treatment for any reason and start another treatment of their 
malignancy, all subsequent response assessments from the date of start of another treatment will 
be excluded from the analysis. 
5.4.1. 
Primary Efficacy Analysis 
The primary statistical analysis of efficacy will be performed on the objective response rate 
(ORR).  The ORR will be presented by dose level and overall with corresponding 90% 
confidence intervals (CIs) using the Wilson method.   
Relevant Output 
Table 14.2.1.1.1 
Objective Response Rate Primary Efficacy Analysis (ITT/Safety Population) 
Table 14.2.1.1.2 
Objective Response Rate Primary Efficacy Analysis (PP Population) 
Listing 16.2.6.1 
Disease Response 
Listing 16.2.6.2A 
Disease Assessment – Part 1 
Listing 16.2.6.2B 
Disease Assessment – Part 2 
5.4.2. 
Secondary Efficacy Analyses 
The following parameters will be analyzed by dose level and overall. Time-to-event analyses 
will use the Kaplan- Meier (KM) method for estimation of summary statistics, and include the 
25th, 50th (median) and 75th percentiles, associated 90% CIs on the median and other 
percentiles, and proportion of censored subjects. A corresponding KM curve will be presented 
for each time-to-event parameter.  
•
Best overall response. The number and percentage of subjects in each response category will
be summarized.
•
Duration of objective response (DOR) – Number of days from the first occurrence of
objective response to the first documented evidence of disease progression. Subjects who
have not progressed prior to the data cut-off for final efficacy analysis, who drop out prior to
study end, or who pass away prior to documentation of disease progression will be censored
at the date of the last valid disease assessment. The DOR analysis will use the KM method
as described above.
•
Time to progression (TTP) – Number of days from the initiation of treatment to disease
progression with deaths due to unrelated causes censored at the date of the last valid disease
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assessment. Subjects who have not progressed prior to the data cut-off for final efficacy 
analysis, or who drop out prior to study end, will be censored at the date of the last valid 
disease assessment. The TTP analysis will use the KM method as described above. 
• Progression-free survival (PFS) – Number of days from the initiation of treatment to disease 
progression or death from any cause. Subjects who have not progressed prior to the data cut-
off for final efficacy analysis, or who drop out prior to study end, will be censored at the 
date of the last valid disease assessment. The PFS analysis will use the KM method as 
described above. 
• Time to best observed response – Number of days from the initiation of treatment to best 
observed category of response. Patients who do not have a response recorded will be 
censored at date of first treatment dose.  The time to best observed response analysis will use 
the KM method as described above. 
• Percent and absolute change in quantitative serum levels of total IgM. - Descriptive 
statistics, including change over time will be presented by dose group and overall. A figure 
representing mean value will be presented with standard deviation as error bars will also be 
presented.  
A repeated measures mixed model will be performed for the change in quantitative serum levels 
of total IgM.  The model will include dose group, study day, the interaction of dose group and 
study day, baseline value of the respective outcome variable and MyD88 mutation status as 
independent variables.  Parameters will initially be analyzed without transformation, but if the 
data suggest otherwise, log transformation may be applied.  The data will be examined by the 
statistician to identify the shape of the relationship between dose and time and the model may be 
adjusted accordingly.  This may include treatment of time as a categorical or continuous 
variable, adding a quadratic term to the model, etc.  In the case that the interaction between dose 
group and study day is not statistically significant at the one-sided 0.10 level, the interaction 
may be excluded from the model. 
The treatment effect will be reported for each dosing cohort including the least square mean 
estimates and the 90% confidence interval.  If the overall test for treatment effect is statistically 
significant at the one-sided 0.10 level, pairwise comparisons will be performed using one-sided 
type I error rates of 0.10 for each comparison. Graphs of the least square mean estimates over 
time will be presented with standard error as error bars.  
Relevant Output 
Table 14.2.1.2.1 
Best Overall Response Secondary Efficacy Analysis (ITT/Safety Population) 
Table 14.2.1.2.2 
Best Overall Response Secondary Efficacy Analysis (PP Population) 
Table 14.2.1.3.1 
Duration of Objective Response Secondary Efficacy Analysis (PP Population) 
Figure 14.2.1.3.1 
Duration of Objective Response Secondary Efficacy Analysis Kaplan-Meier Curve 
(PP Population) 
Table 14.2.1.4.1 
Time to Progression Secondary Efficacy Analysis (ITT/Safety Population) 
Figure 14.2.1.4.1   Time to Progression Secondary Efficacy Analysis Kaplan-Meier Curve (ITT/Safety 
Population) 
Table 14.2.1.4.2 
Time to Progression Secondary Efficacy Analysis (PP Population) 
Figure 14.2.1.4.2  
Time to Progression Secondary Efficacy Analysis Kaplan-Meier Curve (PP 
Population) 
Table 14.2.1.5.1 
Progression-Free Survival Secondary Efficacy Analysis (PP Population) 
Figure 14.2.1.5.1  
Progression-Free Survival Secondary Efficacy Analysis Kaplan-Meier Curve (PP 
Population) 
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Table 14.2.1.6.1 
Time to Best Observed Response Secondary Efficacy Analysis (PP Population) 
Figure 14.2.1.6.1   Time to Best Observed Response Secondary Efficacy Analysis Kaplan-Meier Curve 
(PP Population) 
 
Table 14.2.3.1.1 
Percent Change from Baseline in Quantitative Serum Levels of Total IgM 
(ITT/Safety Population) 
Figure 14.2.3.1.1  
Percent Change from Baseline in Quantitative Serum Levels of Total IgM Box Plot 
(ITT/Safety Population) 
Table 14.2.3.1.2 
Percent Change from Baseline in Quantitative Serum Levels of Total IgM (PP 
Population) 
Figure 14.2.3.1.2  
Percent Change from Baseline in Quantitative Serum Levels of Total IgM Box Plot 
(PP Population) 
Table 14.2.3.2.1 
Change from Baseline in Quantitative Serum Levels of Total IgM (ITT/Safety 
Population) 
Figure 14.2.3.2.1  
Change from Baseline in Quantitative Serum Levels of Total IgM Box Plot 
(ITT/Safety Population) 
Table 14.2.3.2.2 
Change from Baseline in Quantitative Serum Levels of Total IgM (PP Population) 
Figure 14.2.3.2.2  
Change from Baseline in Quantitative Serum Levels of Total IgM Box Plot (PP 
Population) 
Table 14.2.5.1.1 
Change in Quantitative Serum Levels of Total IgM – Repeated Measures Analysis 
(ITT/Safety Population) 
Table 14.2.5.1.2 
Change in Quantitative Serum Levels of Total IgM – Repeated Measures Analysis 
(PP Population) 
Table 14.2.5.2.1 
Change in Quantitative Serum Levels of Total IgM – Repeated Measures Analysis 
Least Square Means by Visit (ITT/Safety Population) 
Figure 14.2.5.2.1   Change in Quantitative Serum Levels of Total IgM - Repeated Measures Analysis: 
Least Square Means over Time (ITT/Safety Population) 
Table 14.2.5.2.2 
Change in Quantitative Serum Levels of Total IgM – Repeated Measures Analysis 
Least Square Means by Visit (PP Population) 
Figure 14.2.5.2.2   Change in Quantitative Serum Levels of Total IgM - Repeated Measures Analysis: 
Least Square Means over Time (PP Population) 
Listing 16.2.6.1 
Disease Response 
Listing 16.2.6.2A 
Disease Assessment – Part 1 
Listing 16.2.6.2B 
Disease Assessment – Part 2 
Listing 16.2.8.9 
Immunoglobin (IgM) Results 
 
5.4.3. 
Exploratory Analyses 
The following investigational factors will be analyzed with regard to disease status and 
presented both globally across all cohorts and by dose level. 
• Presence or absence of MyD88 L265P mutation in tumor cells – Selected efficacy analyses 
described above will be repeated by mutation status subpopulation.  
• Serum cytokine levels - Descriptive statistics, including change over time will be presented 
by visit.  
• Serum levels of antibody to IMO-8400 – Number and percent of subjects with antibody 
present will be presented by visit. 
Additional exploratory analysis may occur. 
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Relevant Output 
Table 14.2.2.1.1 
Objective Response Rate Primary Efficacy Analysis by MyD88 Mutation Status 
(ITT/Safety Population) 
Table 14.2.2.1.2 
Objective Response Rate Primary Efficacy Analysis by MyD88 Mutation Status (PP 
Population) 
Table 14.2.2.2.1 
Best Overall Response Secondary Efficacy Analysis by MyD88 Mutation Status (PP 
Population) 
Table 14.2.2.4.1 
Time to Progression Secondary Efficacy Analysis by MyD88 Mutation Status (PP 
Population) 
Figure 14.2.2.4.1  
Time to Progression Secondary Efficacy Analysis by MyD88 Mutation Status 
Kaplan-Meier Curve (PP Population) 
Table 14.2.4.1.1 
Percent Change from Baseline in Quantitative Serum Levels of Total IgM by 
MyD88 Mutation Status (PP Population) 
Figure 14.2.4.1.1   Percent Change from Baseline in Quantitative Serum Levels of Total IgM by 
MyD88 Mutation Status Box Plot (PP Population) 
Table 14.2.4.2.1 
Change from Baseline in Quantitative Serum Levels of Total IgM by MyD88 
Mutation Status (PP Population) 
Figure 14.2.4.2.1   Change from Baseline in Quantitative Serum Levels of Total IgM by MyD88 
Mutation Status Box Plot (PP Population) 
 
Listing 16.2.4.5 
MyD88 L265P Mutation Status 
Listing 16.2.8.8 
Serum Cytokines Test 
Listing 16.2.8.10 
Serum Antibody Results 
 
5.5. 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be conducted using the PK population. 
Blood samples for plasma levels of IMO-8400 will be collected as scheduled. Samples will be 
analyzed for IMO-8400 concentration using a ligand binding (hybridization) bioanalytical 
method (estimated sensitivity, 20 ng/mL). Pharmacokinetic data will be summarized 
descriptively by dose group and overall.  
Plasma concentrations below the limit of quantification (BQL) will be assigned a value of zero 
when they precede the first quantifiable sample. Any BQL values embedded between 2 
quantifiable data points will be treated as missing. Missing values will not be imputed, and if 
sufficient data are missing for a given subject, that subject may be considered non-evaluable for 
pharmacokinetic analysis. 
Summary statistics will be provided for each of these PK parameters by dose group and overall.  
The geometric mean and %CV will be presented for AUC0-last, Cmax, and RA.  The geometric mean 
and range will be presented for Tmax. 
Figures displaying the mean concentration over time, geometric mean with error bars, and per-
subject concentration by time (with a separate line per subject) will be presented. 
All plasma concentration data per-subject will be displayed in data listings.  
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Relevant Output 
Table 14.2.8.1.1 
Summary of Pharmacokinetic Concentrations by Visit and Timepoint (PK 
Population) 
Table 14.2.8.1.2 
Summary of Pharmacokinetic Parameters by Visit (PK Population) 
Listing 16.2.5.2 
Pharmacokinetic Concentrations 
Listing 16.2.5.3 
Pharmacokinetic Parameters 
 
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6. 
CHANGES TO PLANNED ANALYSES 
Protocol Section 13.3.2.1 identifies the primary treatment effect parameter as the distribution of 
response classes. In this document, the primary treatment effect parameter is identified as the 
overall response rate, as this effect parameter was used during the sample size calculations 
described in Protocol Section 13.1. The distribution of response classes has been identified as a 
secondary efficacy parameter in this document.  
Levels of MyD88 expression in tumor cells is identified in the protocol as an exploratory 
objective and anlysis. MyD88 is analyzed as a categorical factor (mutation present or absent), 
rather than continuous levels of expression.  
Protocol Sections 2.7.1 and 10.8 state that PK data will be analyzed on a population basis. In 
this document it is described the analysis will not be a population PK analysis; it will be a 
standard non-compartmental PK analysis. 
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7. 
REFERENCES 
 
Dimopoulos MA, Gertz, MA, Kastritis E, et al. Update on Treatment Recommendations from 
the Fourth International Workshop on Waldenström’s Macroglobulinemia. J Clin Oncol. 
2008; 27: 1-8. 
 
Kimby E, Treon SP, Anagnostopoulos A, et al. Update on Recommendations for Assessing 
Response from the Third International Workshop on Waldenström’s Macroglobulinemia. 
Clin Lymphoma & Myeloma. 2006; 6: 380-383. 
 
Lim K-H, Barton GM, Staudt LM. Oncogenic MYD88 mutants require Toll-like receptors. 
Amer Assoc Cancer Res, 2013 Annual Meeting, Abstract 2332. 
 
Owen RG, Kyle RA, Stone MJ, et al. Response Assessment in Waldenström’s 
Macroglobulinemia: update from the VIth International Workshop. Br J Haematology 2012; 
160:171-176. 
 
Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s 
macroglobulinemia. N Engl J Med. 2012;367(9):826–833. 
 
Young RM, Staudt LM. Targeting pathologic B cell receptor signaling in lymphoid 
malignancies. Nature Rev Drug Discovery. 2013; 12:229-243. 
 
 
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8. 
CLINICAL STUDY REPORT APPENDICES 
8.1. 
List of Statistical Tables, Figures, and Listings to be Generated 
Table 14.0.1  Treatment Codes Applicable to Tables and Listings ....................................... 43 
Table 14.0.2  SI - US Unit Conversion ..................................................................................... 44 
Table 14.0.3  Laboratory Normal Ranges (US) ....................................................................... 45 
Table 14.1.1.1  Patient Enrollment and Disposition ............................................................... 46 
Table 14.1.2.1  Demographic Characteristics (ITT/Safety Population) ................................ 48 
Table 14.1.2.2  Baseline Characteristics (ITT/Safety Population)......................................... 49 
Table 14.1.3.1  Disease History (ITT/Safety Population) ....................................................... 50 
Table 14.1.4.1  Prior Treatments (ITT/Safety Population) .................................................... 51 
Table 14.2.1.1.1  Objective Response Rate Primary Efficacy Analysis 
(ITT/Safety Population)................................................................................................. 52 
Table 14.2.1.1.2  Objective Response Rate Primary Efficacy Analysis (PP 
Population)...................................................................................................................... 52 
Table 14.2.1.2.1  Best Overall Response Secondary Efficacy Analysis 
(ITT/Safety Population)................................................................................................. 53 
Table 14.2.1.2.2  Best Overall Response Secondary Efficacy Analysis (PP 
Population)...................................................................................................................... 53 
Table 14.2.1.3.1  Duration of Objective Response Secondary Efficacy Analysis 
(PP Population) .............................................................................................................. 54 
Figure 14.2.1.3.1  Duration of Objective Response Secondary Efficacy Analysis 
Kaplan-Meier Curve (PP Population) ......................................................................... 54 
Table 14.2.1.4.1  Time to Progression Secondary Efficacy Analysis 
(ITT/Safety Population)................................................................................................. 55 
Figure 14.2.1.4.1  Time to Progression Secondary Efficacy Analysis Kaplan-
Meier Curve (ITT/Safety Population) .......................................................................... 55 
Table 14.2.1.4.2  Time to Progression Secondary Efficacy Analysis 
(PP Population) .............................................................................................................. 55 
Figure 14.2.1.4.2  Time to Progression Secondary Efficacy Analysis Kaplan-
Meier Curve (PP Population) ....................................................................................... 55 
Table 14.2.1.5.1  Progression-Free Survival Secondary Efficacy Analysis (PP 
Population)...................................................................................................................... 56 
Figure 14.2.1.5.1  Progression-Free Survival Secondary Efficacy Analysis 
Kaplan-Meier Curve (PP Population) ......................................................................... 56 
Table 14.2.1.6.1  Time to Best Observed Response Secondary Efficacy Analysis 
(PP Population) .............................................................................................................. 57 
Figure 14.2.1.6.1  Time to Best Observed Response Secondary Efficacy Analysis 
Kaplan-Meier Curve (PP Population) ......................................................................... 57 
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Table 14.2.2.1.1  Objective Response Rate Primary Efficacy Analysis by 
MyD88 Mutation Status (ITT/Safety Population) ...................................................... 58 
Table 14.2.2.1.2  Objective Response Rate Primary Efficacy Analysis by 
MyD88 Mutation Status (PP Population) .................................................................... 58 
Table 14.2.2.2.1  Best Overall Response Secondary Efficacy Analysis by MyD88 
Mutation Status (PP Population) .................................................................................. 59 
Table 14.2.2.4.1  Time to Progression Secondary Efficacy Analysis by MyD88 
Mutation Status (PP Population) .................................................................................. 60 
Figure 14.2.2.4.1  Time to Progression Secondary Efficacy Analysis by MyD88 
Mutation Status Kaplan-Meier Curve (PP Population) ............................................. 60 
Table 14.2.3.1.1  Percent Change from Baseline in Quantitative Serum Levels 
of Total IgM (ITT/Safety Population) .......................................................................... 61 
Figure 14.2.3.1.1  Percent Change from Baseline in Quantitative Serum Levels 
of Total IgM Box Plot (ITT/Safety Population) .......................................................... 61 
Table 14.2.3.1.2  Percent Change from Baseline in Quantitative Serum Levels 
of Total IgM (PP Population)........................................................................................ 61 
Figure 14.2.3.1.2  Percent Change from Baseline in Quantitative Serum Levels 
of Total IgM Box Plot (PP Population) ........................................................................ 61 
Table 14.2.3.2.1  Change from Baseline in Quantitative Serum Levels of Total 
IgM (ITT/Safety Population) ........................................................................................ 63 
Figure 14.2.3.2.1  Change from Baseline in Quantitative Serum Levels of Total 
IgM Box Plot (ITT/Safety Population) ......................................................................... 63 
Table 14.2.3.2.2  Change from Baseline in Quantitative Serum Levels of Total 
IgM (PP Population) ...................................................................................................... 63 
Figure 14.2.3.2.2  Change from Baseline in Quantitative Serum Levels of Total 
IgM Box Plot (PP Population) ...................................................................................... 63 
Table 14.2.4.1.1  Percent Change from Baseline in Quantitative Serum Levels 
of Total IgM by MyD88 Mutation Status (PP Population) ........................................ 65 
Figure 14.2.4.1.1  Percent Change from Baseline in Quantitative Serum Levels 
of Total IgM by MyD88 Mutation Status Box Plot (PP Population) ........................ 65 
Table 14.2.4.2.1  Change from Baseline in Quantitative Serum Levels of Total 
IgM by MyD88 Mutation Status (PP Population) ...................................................... 67 
Figure 14.2.4.2.1  Change from Baseline in Quantitative Serum Levels of Total 
IgM by MyD88 Mutation Status Box Plot (PP Population) ....................................... 67 
Table 14.2.5.1.1  Change in Quantitative Serum Levels of Total IgM – Repeated 
Measures Analysis (ITT/Safety Population) ................................................................ 69 
Table 14.2.5.1.2  Change in Quantitative Serum Levels of Total IgM – Repeated 
Measures Analysis (PP Population) ............................................................................. 69 
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Table 14.2.5.2.1  Change in Quantitative Serum Levels of Total IgM – Repeated 
Measures Analysis Least Square Means by Visit (ITT/Safety 
Population)...................................................................................................................... 70 
Figure 14.2.5.2.1  Change in Quantitative Serum Levels of Total IgM - 
Repeated Measures Analysis: Least Square Means over 
Time(ITT/Safety Population) ........................................................................................ 70 
Table 14.2.5.2.2  Change in Quantitative Serum Levels of Total IgM – Repeated 
Measures Analysis (PP Population) ............................................................................. 70 
Figure 14.2.5.2.2  Change in Quantitative Serum Levels of Total IgM - 
Repeated Measures Analysis: Least Square Means over Time 
(PP Population) .............................................................................................................. 70 
Table 14.2.8.1.1  Summary of Pharmacokinetic Concentrations by Visit and 
Timepoint (PK Population) ........................................................................................... 71 
Table 14.2.8.1.2  Summary of Pharmacokinetic Parameters by Visit (PK 
Population)...................................................................................................................... 72 
Table 14.3.1.1  Summary of Adverse Events (ITT/Safety Population) ................................. 73 
Table 14.3.1.2  Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term (ITT/Safety Population) ......................... 74 
Table 14.3.1.3  Incidence of Treatment-Emergent Adverse Events by 
Relationship to Study Drug and by MedDRA System Organ Class and 
Preferred Term (ITT/Safety Population) .................................................................... 75 
Table 14.3.1.4  Incidence of Non-Serious Adverse Events, by MedDRA System 
Organ Class and Preferred Term (Safety Population) ............................................... 77 
Table 14.3.1.5  Incidence of Treatment-Emergent Adverse Events by Intensity 
and by MedDRA System Organ Class and Preferred Term 
(ITT/Safety Population)................................................................................................. 78 
Table 14.3.1.6  Incidence of Dose-Limiting Toxicity Adverse Events by 
MedDRA System Organ Class and Preferred Term (ITT/Safety 
Population)...................................................................................................................... 80 
Table 14.3.1.7  Incidence of Local Injection Site Reactions Worst Grade Post 
Baseline (ITT/Safety Population) ................................................................................. 81 
Table 14.3.1.8  Incidence of Local Injection Site Reactions Worst Grade by 
Visit (ITT/Safety Population)........................................................................................ 82 
Table 14.3.2.1  Listing of Deaths ............................................................................................... 83 
Table 14.3.2.2  Listing of Serious Adverse Events .................................................................. 84 
Table 14.3.2.3  Listing of Treatment Discontinuations Due to Adverse Events ................... 85 
Table 14.3.4.1  Listing of Clinically Significant Abnormal Laboratory Values 
(ITT/ Safety Population)................................................................................................ 86 
Table 14.3.5.1  Study Drug Exposure (ITT/Safety Population) ............................................. 87 
Table 14.3.5.2  Study Drug Exposure (PP Population) .......................................................... 87 
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Table 14.3.5.3  Summary and Change from Baseline for Hematology 
Parameters by Time Point and Dose Group (ITT/Safety Population)...................... 88 
Figure 14.3.5.3  Summary and Change from Baseline for Hematology 
Parameters by Time Point and Dose Group - Box Plot 
(ITT/Safety Population)................................................................................................. 88 
Table 14.3.5.4  Summary and Change from Baseline for Chemistry Parameters 
by Time Point and Dose Group (ITT/Safety Population) .......................................... 88 
Figure 14.3.5.4  Summary and Change from Baseline for Chemistry 
Parameters by Time Point and Dose Group - Box Plot (ITT/Safety 
Population)...................................................................................................................... 88 
Table 14.3.5.5  Summary and Change from Baseline for Coagulation 
Parameters by Time Point and Dose Group (ITT/Safety Population)...................... 88 
Figure 14.3.5.5  Summary and Change from Baseline for Coagulation 
Parameters by Time Point and Dose Group - Box Plot (ITT/Safety 
Population)...................................................................................................................... 88 
Table 14.3.5.6A  Shifts from Baseline to Worst CTC Grade Post-Baseline in 
Hematology Parameters by Dose Group (ITT/Safety Population) ........................... 90 
Table 14.3.5.6B  Shifts from Baseline to Worst CTC Grade Post-Baseline in 
Chemistry Parameters by Dose Group (ITT/Safety Population) .............................. 90 
Table 14.3.5.6C  Shifts from Baseline to Worst CTC Grade Post-Baseline in 
Coagulation Parameters by Dose Group (ITT/Safety Population) ........................... 90 
Table 14.3.5.7  Summary and Change from Baseline for Vital Signs by Time 
Point and Dose Group (ITT/Safety Population) ......................................................... 91 
Figure 14.3.5.7 - Summary and Change from Baseline for Vital Signs by Time 
Point and Dose Group - Box Plot (ITT/Safety Population)........................................ 91 
Table 14.3.5.8  Summary and Change from Baseline for Electrocardiogram 
Results by Time Point and Dose Group (ITT/Safety Population) ............................. 93 
Table 14.3.5.9  Listing of Abnormal Electrocardiogram Assessments 
(ITT/Safety Population)................................................................................................. 95 
Table 14.3.5.10  Concomitant Medications (ITT/Safety Population) .................................... 96 
Listing 16.0.1  System Organ Class Abbreviations ................................................................. 98 
Listing 16.2.1.1  Patients Discontinuing Treatment Prematurely ......................................... 99 
Listing 16.2.1.2  End of Treatment (EOT) Visit Status ........................................................ 100 
Listing 16.2.1.3  End of Study (EOS) Visit Status ................................................................. 101 
Listing 16.2.2.1  Inclusion Criteria ......................................................................................... 102 
Listing 16.2.2.2  Exclusion Criteria ........................................................................................ 103 
Listing 16.2.2.3  Listing of Inclusion/Exclusion Criteria Not Met ....................................... 104 
Listing 16.2.2.4  Intent–To-Treat Patients Excluded from Per-Protocol 
Population ..................................................................................................................... 105 
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Listing 16.2.3  Protocol Deviations ......................................................................................... 106 
Listing 16.2.4.1  Demographic Characteristics ..................................................................... 107 
Listing 16.2.4.2  Medical History ............................................................................................ 108 
Listing 16.2.4.3A  Waldenström’s Macroglobulinemia Disease History – Part 1 .............. 109 
Listing 16.2.4.3B  Waldenström’s Macroglobulinemia Disease History – Part 2 .............. 110 
Listing 16.2.4.4  Prior Waldenström’s Macroglobulinemia Therapy ................................. 111 
Listing 16.2.4.5  MyD88 L265P Mutation Status .................................................................. 112 
Listing 16.2.5.1  Study Drug Exposure .................................................................................. 113 
Listing 16.2.5.2  Pharmacokinetic Concentrations ............................................................... 114 
Listing 16.2.5.3  Pharmacokinetic Parameters ...................................................................... 115 
Listing 16.2.6.1  Disease Response .......................................................................................... 116 
Listing 16.2.6.2A  Disease Assessment – Part 1 ..................................................................... 117 
Listing 16.2.6.2B  Disease Assessment – Part 2 ..................................................................... 118 
Listing 16.2.7.1  Adverse Events by Patient and MedDRA System Organ Class / 
Preferred Term ............................................................................................................ 119 
Listing 16.2.7.2  Adverse Events by MedDRA System Organ Class and 
Preferred Term ............................................................................................................ 120 
Listing 16.2.7.3  Glossary of Adverse Event Verbatim Terms by MedDRA 
System Organ Class, Preferred Term, and Patient .................................................. 121 
Listing 16.2.7.4  Injection Site Reaction Assessments .......................................................... 122 
Listing 16.2.7.5  Patient Reported Injection Site Reactions ................................................. 123 
Listing 16.2.7.6  Observed Injection Site Reactions .............................................................. 124 
Listing 16.2.8.1A  Laboratory Results: Hematology – Part 1 .............................................. 125 
Listing 16.2.8.1B  Laboratory Results: Hematology – Part 2 .............................................. 126 
Listing 16.2.8.2  Laboratory Results: Chemistry .................................................................. 126 
Listing 16.2.8.3  Laboratory Results: Urinalysis ................................................................... 126 
Listing 16.2.8.4  Laboratory Results: Coagulation ............................................................... 126 
Listing 16.2.8.5  Laboratory Results: Serology ..................................................................... 127 
Listing 16.2.8.6  Urine Pregnancy Test Results ..................................................................... 128 
Listing 16.2.8.7  Bone Marrow Biopsy ................................................................................... 129 
Listing 16.2.8.8  Serum Cytokines Test .................................................................................. 130 
Listing 16.2.8.9  Immunoglobulin (IgM) Results .................................................................. 131 
Listing 16.2.8.10  Serum Antibody Results ............................................................................ 132 
Listing 16.2.9.1  Vital Signs ..................................................................................................... 133 
Listing 16.2.9.2  Physical Examination Findings .................................................................. 134 
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Listing 16.2.9.3  Eastern Cooperative Oncology Group (ECOG) Performance 
Status ............................................................................................................................. 135 
Listing 16.2.9.4  12-Lead Electrocardiogram Interval and Overall Assessment ............... 136 
Listing 16.2.9.5  12-Lead Electrocardiogram – Comments on Abnormal 
Assessments .................................................................................................................. 137 
Listing 16.2.9.6  Concomitant Medications ........................................................................... 138 
 
 
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8.2. 
Statistical Table and Figure Shells 
The following statistical tables and figures will be produced. 
 
 
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Protocol 8400-401 
Table 14.0.1 
 
Treatment Codes Applicable to Tables and Listings 
 
Treatment Code 
Treatment Description 
0.6 mg/kg/wk  
IMO-8400 at 0.6 mg/kg/wk 
0.9 mg/kg/wk 
IMO-8400 at 0.9 mg/kg/wk 
1.2 mg/kg/wk 
IMO-8400 at 1.2 mg/kg/wk 
1.8 mg/kg/wk 
IMO-8400 at 1.8 mg/kg/wk 
2.4 mg/kg/wk  
IMO-8400 at 2.4 mg/kg/wk 
Total  
Pooled IMO-8400 dosing groups 
 
Note: Dosing is based on body weight at screening up to a maximum dose representing 125 kg equivalent. 
 
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Table 14.0.2 
 
SI - US Unit Conversion 
 
Lab Type 
Laboratory Test 
Unit Reported 
by Lab 
Conversion Factor: 
Lab to SI Unit 
SI Unit 
Conversion Factor: 
SI to US Unit 
US Unit 
  
  
  
  
  
  
  
 
 
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Table 14.0.3 
 
Laboratory Normal Ranges (US) 
 
Lab Type 
Lab Test 
Lab Name 
Range  
Unit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Page 1 of 2 
Protocol 8400-401 
Table 14.1.1.1 
 
Patient Enrollment and Disposition 
 
Disposition 
Sta-
tistic 
0.6 
mg/kg/wk 
(N=xx) 
0.9 
mg/kg/wk 
(N=xx) 
1.2 
mg/kg/wk 
(N=xx) 
1.8 
mg/kg/wk 
(N=xx) 
2.4 
mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
Total Number of Patients Screened[1] 
n 
xx 
xx 
xx 
xx 
xx 
xx 
Total Number of Screen Failures[2] 
n 
xx 
xx 
xx 
xx 
xx 
xx 
Total Number of Patients Enrolled[3] 
n  
xx 
xx 
xx 
xx 
xx 
xx 
Study Populations 
 
 
 
 
 
 
 
 Safety/ Intent-to-Treat [4] 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 Per-Protocol[5] 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 Pharmacokinetic[6] 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Discontinued Treatment 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Primary Reason for Treatment 
Discontinuation from EOT [7] 
 
 
 
 
 
 
 
 DLT event 
 Disease Progression 
 Completion of 24 Weeks Treatment 
 AE, other than DLT 
 Withdrawal of Consent 
 Lost to Follow-Up 
 Study Terminated by Sponsor 
 Other 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Note: Unless otherwise noted, percentage is based on total number of patients enrolled (treated). 
[1] Screened: Patients who signed consent and underwent screening procedure. 
[2] Screen Failure: Screened patients deemed ineligible to enroll in the study due to failure to comply with incl/excl criteria. 
[3] Enrolled: Patients who received at least one dose of study medication. 
[4] All patients who received at least one dose of the study treatment.  
[5] All patients who have one or more scheduled post-treatment tumor assessments, and no major protocol deviations.  
[6] All patients with evaluable PK data based on protocol compliance, adequate number of samples and successful sample assays. 
[7] EOT = End of Treatment. Percentage based on the number of patients who have discontinued treatment.  
[8] Prematurely Discontinued Treatment: Patients who discontinued treatment prior to 24 weeks. 
[9] EOS = End of Study. Percentage based on the number of patients who have prematurely discontinued treatment.  
Reference Listing: 16.x.x.x 
 
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Page 2 of 2 
Protocol 8400-401 
Table 14.1.1.1 
 
Patient Enrollment and Disposition 
 
Disposition 
Sta-
tistic 
0.6 
mg/kg/wk 
(N=xx) 
0.9 
mg/kg/wk 
(N=xx) 
1.2 
mg/kg/wk 
(N=xx) 
1.8 
mg/kg/wk 
(N=xx) 
2.4 
mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
Prematurely Discontinued Treatment[10] 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Primary Reason for Premature Treatment 
Discontinuation from EOS [11] 
 
 
 
 
 
 
 
 Disease Progression 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 AE, related to study treatment 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 AE, unrelated to study treatment 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 Non-compliance 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 Lost to Follow-Up 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 Physician Decision 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 Study Terminated by Sponsor 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Note: Unless otherwise noted, percentage is based on total number of patients enrolled (treated). 
[1] Screened: Patients who signed consent and underwent screening procedure. 
[2] Screen Failure: Screened patients deemed ineligible to enroll in the study due to failure to comply with incl/excl criteria. 
[3] Enrolled: Patients who received at least one dose of study medication. 
[4] All patients who received at least one dose of the study treatment.  
[5] All patients who have one or more scheduled post-treatment tumor assessments, and no major protocol deviations.  
[6] All patients with evaluable PK data based on protocol compliance, adequate number of samples and successful sample assays. 
[7] Percentage based on the number of patients who have discontinued treatment.  
[8] Prematurely Discontinued Treatment: Patients who discontinued treatment prior to 24 weeks. 
[9] Percentage based on the number of patients who have prematurely discontinued treatment.  
Reference Listing: 16.x.x.x 
 
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Table 14.1.2.1 
 
Demographic Characteristics (ITT/Safety Population) 
 
Parameter 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total  
(N=xx) 
Age (years) [1] 
 
 
 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Ethnicity  
 
Hispanic/Latino 
 
Not Hispanic/ Latino 
 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
Race  
 
American Indian  
 
or Alaska Native 
 
Asian 
 
Black 
 
Native Hawaiian or  
 
Other Pacific Islander 
 
White 
 
Other 
 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
Sex  
 
Male  
 
Female  
 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
[1] Age calculated based on date of informed consent. 
 
Reference Listing: 16.x.x.x 
 
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Table 14.1.2.2 
 
Baseline Characteristics (ITT/Safety Population) 
 
Parameter 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total  
(N=xx) 
Baseline Height (cm) 
 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Baseline Weight (kg) 
 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Baseline BMI (kg/m2) 
[1] 
 
 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Baseline ECOG 
Performance Status 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
MyD88 mutation status
 
Present 
 
Absent 
 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
[1] Body Mass Index = Weight (kg)/(Height (m))2. 
 
Reference Listing: 16.x.x.x 
 
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Table 14.1.3.1 
 
Disease History (ITT/Safety Population) 
 
Parameter 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
Time Since WM Diagnosis 
(yrs) [1] 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
Time Since First 
Treatment for WM (yrs) 
[2] 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
At least 1 Treatment 
Related AE in the past 
3 months 
 
Yes 
 
No 
 
 
 
n (%) 
n (%) 
 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
xx (xx.x) 
xx (xx.x) 
Subject has been 
hospitalized in the 
past year 
  Yes 
 
No 
 
 
 
n (%) 
n (%) 
 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
xx (xx.x) 
xx (xx.x) 
Time since most recent 
hospitalization 
(months) [3] 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
[1] Time from WM diagnosis to date of first dose of study drug. 
[2] Time from date of first treatment for WM to date of first dose of study drug. 
[3] Time from most recent date of discharge to date of first dose of study drug. 
Reference Listing: 16.x.x.x 
 
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Table 14.1.4.1 
 
Prior Treatments (ITT/Safety Population) 
 
Parameter 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
Received at least 1 Prior 
Therapy 
 
Agent/Treatment 
 
 
Rituximab 
 
 
Cyclophosphamide 
 
 
Doxorubicin 
 
 
Vincristine 
 
 
Prednisone 
 
 
Fludarabine 
 
 
Cladribine 
 
 
Other 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Best Overall Response [1] 
 
Complete Response 
 
Very Good Partial  
 
 
Response 
 
Partial Response 
 
Minor Response 
 
Stable Disease 
 
Progressive Disease 
 
Not Evaluable 
 
Delayed Response 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
  
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of Prior Therapies 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
Number of Days since Most 
Recent Prior Therapy [2] 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
[1] Percentages based on number that received at least 1 prior therapy.   
[2] Time from end of prior therapy to date of first dose of IMO-8400. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Number of days since Most Recent Prior Therapy = (date of first dose – end date of most recent prior therapy) + 1 
 
 
 
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Page 52 of 142 
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Page x of y 
Protocol 8400-401 
Table 14.2.1.1.1 
 
Objective Response Rate Primary Efficacy Analysis (ITT/Safety Population) 
 
Parameter 
Sta-
tistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total (N=xx) 
Objective Response Rate  
(CR/VGPR/PR/MR) 
n (%) 
90%CI 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
Note: CR = Complete response. VGPR = Very good partial response. PR = Partial response. MR = Minor response. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
Repeat for:  
Table 14.2.1.1.2  Objective Response Rate Primary Efficacy Analysis (PP Population) 
  
 
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Page 53 of 142 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.1.2.1 
 
Best Overall Response Secondary Efficacy Analysis (ITT/Safety Population) 
 
Parameter 
Statistic 
0.6 
mg/kg/wk 
(N=xx) 
0.9 
mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total (N=xx) 
Best Overall Response 
 
Complete response 
 
Very good partial response 
 
Partial response 
 
Minor response 
 
Stable disease 
 
Progressive disease 
 
Not evaluable 
 
Delayed response 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Repeat on PP population only if the difference in number of patients between ITT and PP populations is >2. 
 
Repeat for:  
Table 14.2.1.2.2  Best Overall Response Secondary Efficacy Analysis (PP Population) 
 
 
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Page 54 of 142 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.1.3.1 
 
Duration of Objective Response Secondary Efficacy Analysis (PP Population) 
 
Parameter 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total (N=xx) 
Duration of 
Objective 
Response (DOR) 
75th Percentile  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
Median  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
 
25th Percentile 
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
Censored 
Observations 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Events 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: Subjects who have not progressed prior to the data cut-off for final efficacy analysis, who drop out prior to study end, or who 
pass away prior to documentation of disease progression will be censored at the date of the last valid disease assessment. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Figure: 
Figure 14.2.1.3.1  Duration of Objective Response Secondary Efficacy Analysis Kaplan-Meier Curve (PP Population) 
 
 
 
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Page 55 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.1.4.1 
 
Time to Progression Secondary Efficacy Analysis (ITT/Safety Population) 
 
Parameter 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total (N=xx) 
Time to 
Progression (TTP) 
75th Percentile  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
Median  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
 
25th Percentile 
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
Censored 
Observations 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Events 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: Subjects who have not progressed prior to the data cut-off for final efficacy analysis, or who drop out prior to study end, will 
be censored at the day they were last known to be progression-free date of the last valid disease assessment. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Repeat on PP population only if the difference in number of patients between ITT and PP populations is >2. 
 
Figure: 
  Figure 14.2.1.4.1  Time to Progression Secondary Efficacy Analysis Kaplan-Meier Curve (ITT/Safety Population) 
 
Repeat for: 
  Table 14.2.1.4.2  Time to Progression Secondary Efficacy Analysis (PP Population) 
  Figure 14.2.1.4.2  Time to Progression Secondary Efficacy Analysis Kaplan-Meier Curve (PP Population) 
 
 
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Statistical Analysis Plan 
 
Page 56 of 142 
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Page x of y 
Protocol 8400-401 
Table 14.2.1.5.1 
 
Progression-Free Survival Secondary Efficacy Analysis (PP Population) 
 
Parameter 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total (N=xx) 
Progression-Free 
Survival (PFS) 
75th Percentile  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
Median  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
 
25th Percentile 
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
Censored 
Observations 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Events 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: Subjects who have not progressed prior to the data cut-off for final efficacy analysis, or who drop out prior to study end, will 
be censored at the date of the last valid disease assessment. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Figure: 
  Figure 14.2.1.5.1  Progression-Free Survival Secondary Efficacy Analysis Kaplan-Meier Curve (PP Population) 
 
 
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Statistical Analysis Plan 
 
Page 57 of 142 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.1.6.1 
 
Time to Best Observed Response Secondary Efficacy Analysis (PP Population) 
 
Parameter 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total (N=xx) 
Time to Best 
Observed Response 
75th Percentile  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
Median  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
 
25th Percentile 
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
Censored 
Observations 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Events 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: Patients who do not have a response recorded will be censored at date of first treatment dose.  
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Figure: 
  Figure 14.2.1.6.1  Time to Best Observed Response Secondary Efficacy Analysis Kaplan-Meier Curve (PP Population) 
  
 
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Statistical Analysis Plan 
 
Page 58 of 142 
Protocol 8400-401, Final Version 1.0 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.2.1.1 
 
Objective Response Rate Primary Efficacy Analysis by MyD88 Mutation Status (ITT/Safety Population) 
 
Parameter 
Mutation 
Status 
Sta-
tistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
Objective Response 
Rate (CR/VGPR/PR/MR) 
Present 
n(%) 
90% CI 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
 
Absent 
n (%) 
90% CI 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
Note: CR = Complete response. VGPR = Very good partial response. PR = Partial response. MR = Minor response. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Repeat on PP population only if the difference in number of patients between ITT and PP populations is >2. 
 
Repeat for:  
  Table 14.2.2.1.2  Objective Response Rate Primary Efficacy Analysis by MyD88 Mutation Status (PP Population) 
 
 
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Statistical Analysis Plan 
 
Page 59 of 142 
Protocol 8400-401, Final Version 1.0 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.2.2.1 
 
Best Overall Response Secondary Efficacy Analysis by MyD88 Mutation Status (PP Population) 
 
Mutation 
Status 
Best Overall Response 
Sta-
tistic 
0.6 
mg/kg/wk 
(N=xx) 
0.9 
mg/kg/wk 
(N=xx) 
1.2 
mg/kg/wk 
(N=xx) 
1.8 
mg/kg/wk 
(N=xx) 
2.4 
mg/kg/wk 
(N=xx) 
Total (N=xx) 
Present 
Complete response 
Very good partial response 
Partial response 
Minor response 
Stable disease 
Progressive disease 
Not evaluable 
Delayed response 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Absent 
Complete response 
Very good partial response 
Partial response 
Minor response 
Stable disease 
Progressive disease 
Not evaluable 
Delayed response 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
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Statistical Analysis Plan 
 
Page 60 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.2.4.1 
 
Time to Progression Secondary Efficacy Analysis by MyD88 Mutation Status (PP Population) 
 
Mutation 
Status 
Parameter 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total (N=xx) 
Present 
TTP 
75th Percentile  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
 
Median  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
 
 
25th Percentile 
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
 
Censored 
Observations 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Event Rate 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Absent 
TTP 
75th Percentile  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
 
 
Median  
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
 
 
25th Percentile 
(90% CI) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
xx.x 
(xx.x, xx.x) 
 
Censored 
Observations 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Event Rate 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: TTP = Time to Progression. Subjects who have not progressed prior to the data cut-off for final efficacy analysis, or who drop 
out prior to study end, are censored at the day they were last known to be progression-free date of the last valid disease assessment. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Figure: 
  Figure 14.2.2.4.1  Time to Progression Secondary Efficacy Analysis by MyD88 Mutation Status Kaplan-Meier Curve (PP Population) 
  
 
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Statistical Analysis Plan 
 
Page 61 of 142 
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13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.2.3.1.1 
 
Percent Change from Baseline in Quantitative Serum Levels of Total IgM (ITT/Safety Population) 
 
0.6 mg/kg/wk (N=xx) 
0.9 mg/kg/wk (N=xx) 
1.2 mg/kg/wk (N=xx) 
Visit 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
C1W9 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc. 
 
  
 
  
 
Note: Baseline = the most recent laboratory assessments before the first dose of study medication. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Move onto 2 pages as needed; include all dose groups and total (0.6, 0.9, 1.2, 1.8, 2.4, and total), see following 
page. For the Box plot figures, include standard deviation as error bars. 
Programming note: Repeat on PP population only if the difference in number of patients between ITT and PP populations is >2. 
 
Figure: 
  Figure 14.2.3.1.1  Percent Change from Baseline in Quantitative Serum Levels of Total IgM Box Plot (ITT/Safety Population) 
 
Repeat for: 
  Table 14.2.3.1.2  Percent Change from Baseline in Quantitative Serum Levels of Total IgM (PP Population) 
  Figure 14.2.3.1.2  Percent Change from Baseline in Quantitative Serum Levels of Total IgM Box Plot (PP Population) 
 
 
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Statistical Analysis Plan 
 
Page 62 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page 2 of y 
Protocol 8400-401 
Table 14.2.3.1.1 
 
Percent Change from Baseline in Quantitative Serum Levels of Total IgM (ITT/Safety Population) 
 
1.8 mg/kg/wk (N=xx) 
2.4 mg/kg/wk (N=xx) 
Total (N=xx) 
Visit 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
C1W9 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc. 
 
  
 
  
 
Note: Baseline = the most recent laboratory assessments before the first dose of study medication. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
62-289


Statistical Analysis Plan 
 
Page 63 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.2.3.2.1 
 
Change from Baseline in Quantitative Serum Levels of Total IgM (ITT/Safety Population) 
 
0.6 mg/kg/wk (N=xx) 
0.9 mg/kg/wk (N=xx) 
1.2 mg/kg/wk (N=xx) 
Visit 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
C1W9 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc. 
 
  
 
  
 
Note: Baseline = the most recent laboratory assessments before the first dose of study medication. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Move onto 2 pages as needed; include all dose groups and total (0.6, 0.9, 1.2, 1.8, 2.4, and total), see following 
page. For the Box plot figures, include standard deviation as error bars. 
Programming note: Repeat on PP population only if the difference in number of patients between ITT and PP populations is >2. 
 
Figure: 
  Figure 14.2.3.2.1  Change from Baseline in Quantitative Serum Levels of Total IgM Box Plot (ITT/Safety Population) 
 
Repeat for: 
  Table 14.2.3.2.2  Change from Baseline in Quantitative Serum Levels of Total IgM (PP Population) 
  Figure 14.2.3.2.2  Change from Baseline in Quantitative Serum Levels of Total IgM Box Plot (PP Population) 
 
 
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Statistical Analysis Plan 
 
Page 64 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page 2 of y 
Protocol 8400-401 
Table 14.2.3.2.1 
 
Change from Baseline in Quantitative Serum Levels of Total IgM (ITT/Safety Population) 
 
1.8 mg/kg/wk (N=xx) 
2.4 mg/kg/wk (N=xx) 
Total (N=xx) 
Visit 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
C1W9 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc. 
 
  
 
  
 
Note: Baseline = the most recent laboratory assessments before the first dose of study medication. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
64-289


Statistical Analysis Plan 
 
Page 65 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.2.4.1.1 
 
Percent Change from Baseline in Quantitative Serum Levels of Total IgM by MyD88 Mutation Status (PP Population) 
 
 
0.6 mg/kg/wk (N=xx) 
0.9 mg/kg/wk (N=xx) 
1.2 mg/kg/wk (N=xx) 
Visit 
Mutation 
Status 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Baseline 
Present 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
Absent 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
C1W9 
Present 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Absent 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc.  
 
 
 
 
  
 
  
 
Note: Baseline = the most recent laboratory assessments before the first dose of study medication. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Move onto 2 pages as needed; include all dose groups and total (0.6, 0.9, 1.2, 1.8, 2.4, and total), see following 
page. For the Box plot figures, include standard deviation as error bars. 
 
Figure: 
Figure 14.2.4.1.1  Percent Change from Baseline in Quantitative Serum Levels of Total IgM by MyD88 Mutation Status Box Plot (PP 
Population) 
 
 
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Confidential and Proprietary 
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Statistical Analysis Plan 
 
Page 66 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page 2 of y 
Protocol 8400-401 
Table 14.2.4.1.1 
 
Percent Change from Baseline in Quantitative Serum Levels of Total IgM by MyD88 Mutation Status (PP Population) 
 
 
1.8 mg/kg/wk (N=xx) 
2.4 mg/kg/wk (N=xx) 
Total (N=xx) 
Visit 
Mutation 
Status 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Baseline 
Present 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
Absent 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
C1W9 
Present 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Absent 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc.  
 
 
 
 
  
 
  
 
Note: Baseline = the most recent laboratory assessments before the first dose of study medication. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
66-289


Statistical Analysis Plan 
 
Page 67 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.2.4.2.1 
 
Change from Baseline in Quantitative Serum Levels of Total IgM by MyD88 Mutation Status (PP Population) 
 
 
0.6 mg/kg/wk (N=xx) 
0.9 mg/kg/wk (N=xx) 
1.2 mg/kg/wk (N=xx) 
Visit 
Mutation 
Status 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Baseline 
Present 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
Absent 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
C1W9 
Present 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Absent 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc.  
 
 
 
 
  
 
  
 
Note: Baseline = the most recent laboratory assessments before the first dose of study medication. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Move onto 2 pages as needed; include all dose groups and total (0.6, 0.9, 1.2, 1.8, 2.4, and total), see following 
page. For the Box plot figures, include standard deviation as error bars. 
 
Figure: 
  Figure 14.2.4.2.1  Change from Baseline in Quantitative Serum Levels of Total IgM by MyD88 Mutation Status Box Plot (PP Population) 
 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
67-289


Statistical Analysis Plan 
 
Page 68 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page 2 of y 
Protocol 8400-401 
Table 14.2.4.2.1 
 
Change from Baseline in Quantitative Serum Levels of Total IgM by MyD88 Mutation Status (PP Population) 
 
 
1.8 mg/kg/wk (N=xx) 
2.4 mg/kg/wk (N=xx) 
Total (N=xx) 
Visit 
Mutation 
Status 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Baseline 
Present 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
Absent 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
C1W9 
Present 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Absent 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc.  
 
 
 
 
  
 
  
 
Note: Baseline = the most recent laboratory assessments before the first dose of study medication. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
68-289


Statistical Analysis Plan 
 
Page 69 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.5.1.1 
 
Change in Quantitative Serum Levels of Total IgM – Repeated Measures Analysis (ITT/Safety Population) 
 
Parameter 
Statistic  
Global 
Test [1] 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Visit 
p-value 
0.xxxx 
 
 
 
 
 
Treatment 
p-value 
0.xxxx 
 
 
 
 
 
Treatment*Visit 
p-value 
0.xxxx 
 
 
 
 
 
Baseline Value 
p-value 
0.xxxx 
 
 
 
 
 
 
 
 
 
 
 
Dose group vs. 0.6 
mg/kg/wk 
Estimate [2] 
90% CI  
P-value  
NA 
NA 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
Dose group vs. 0.9 
mg/kg/wk 
Estimate 
90% CI  
P-value  
NA 
x.xx 
x.x, x.x 
0.xxxx 
NA 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
Dose group vs. 1.2 
mg/kg/wk 
Estimate 
90% CI  
P-value  
NA 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
NA 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
Dose group vs. 1.8 
mg/kg/wk 
Estimate 
90% CI  
P-value  
NA 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
NA 
x.xx 
x.x, x.x 
0.xxxx 
Dose group vs. 2.4 
mg/kg/wk 
Estimate 
90% CI  
P-value  
NA 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
x.xx 
x.x, x.x 
0.xxxx 
NA 
Note: Model based on a repeated-measures mixed-model (PROC MIXED in SAS) with response variable change from baseline, fixed factors 
for treatment, visit and treatment by visit interaction, and baseline value and MyD88 mutation status as covariates.                                  
[1] Type 3 tests (Global F test) 
[2] Footnote where estimate/ p-value is coming from    
NA = Not applicable. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Compare the individual dose groups only if the global test is statistically significant.  
Programming note: Repeat on PP population only if the difference in number of patients between ITT and PP populations is >2. 
 
Repeat for: 
  Table 14.2.5.1.2  Change in Quantitative Serum Levels of Total IgM – Repeated Measures Analysis (PP Population) 
 
 
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Page x of y 
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Table 14.2.5.2.1 
 
Change in Quantitative Serum Levels of Total IgM – Repeated Measures Analysis Least Square Means by Visit (ITT/Safety Population) 
 
Visit  
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Day 1 
LS Means 
SE 
90% CI 
x.x 
x.xx 
x.x, x.x 
 
x.x 
x.xx 
x.x, x.x 
 
x.x 
x.xx 
x.x, x.x 
 
x.x 
x.xx  
x.x, x.x 
x.x 
x.xx  
x.x, x.x 
Day 15 
LS Means 
SE 
90% CI 
 
x.x 
x.xx 
x.x, x.x 
 
x.x 
x.xx 
x.x, x.x 
 
x.x 
x.xx 
x.x, x.x 
 
x.x 
x.xx  
x.x, x.x 
x.x 
x.xx  
x.x, x.x 
Etc.  
LS Means 
SE 
90% CI 
x.x 
x.xx 
x.x, x.x 
x.x 
x.xx 
x.x, x.x 
x.x 
x.xx 
x.x, x.x 
x.x 
x.xx  
x.x, x.x 
x.x 
x.xx  
x.x, x.x 
Note: LS = Least-squares. SE = Standard Error. CI = Confidence Interval. Model based on a repeated-measures mixed-model (PROC MIXED in 
SAS) with response variable change from baseline, fixed factors for treatment, visit and treatment by visit interaction, and baseline 
value and MyD88 mutation status as covariates. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Present the least square means estimate figures with standard deviation as error bars.  
Programming note: Repeat on PP population only if the difference in number of patients between ITT and PP populations is >2. 
 
Figure: 
  Figure 14.2.5.2.1  Change in Quantitative Serum Levels of Total IgM - Repeated Measures Analysis: Least Square Means over 
Time(ITT/Safety Population) 
 
Repeat for:  
Table 14.2.5.2.2  Change in Quantitative Serum Levels of Total IgM – Repeated Measures Analysis (PP Population) 
Figure 14.2.5.2.2  Change in Quantitative Serum Levels of Total IgM - Repeated Measures Analysis: Least Square Means over Time 
(PP Population) 
 
 
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Statistical Analysis Plan 
 
Page 71 of 142 
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Confidential 
Page x of y 
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Table 14.2.8.1.1 
 
Summary of Pharmacokinetic Concentrations by Visit and Timepoint (PK Population) 
 
Visit 
Timepoint 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
Day 1 
Pre-dose 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
1 hour 
post-dose 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
2 hours 
post-dose 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
4 hours 
post-dose 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
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Page 72 of 142 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.8.1.2 
 
Summary of Pharmacokinetic Parameters by Visit (PK Population) 
 
Parameter 
Visit 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
Cmax 
(ng/mL) 
Day 1 
n 
Mean (SD) 
Median 
Min,Max  
CV% 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
 
Day 15 
n 
Mean (SD) 
Median 
Min,Max  
CV% 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
 
Etc. 
 
 
 
 
 
 
 
AUC0-last 
Day 1 
n 
Mean (SD) 
Median 
Min,Max  
CV% 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
 
Etc. 
 
 
 
 
 
 
 
Tmax 
Day 1 
n 
Mean (SD) 
Median 
Min,Max  
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Etc. 
 
 
 
 
 
 
 
RA 
Day 1 
n 
Mean (SD) 
Median 
Min,Max  
CV% 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
 
Etc. 
 
 
 
 
 
 
 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Include all visits and PK parameters. 
 
 
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Page 73 of 142 
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Page x of y 
Protocol 8400-401 
Table 14.3.1.1 
 
Summary of Adverse Events (ITT/Safety Population) 
 
Parameter 
Sta-
tistic 
0.6 
mg/kg/wk 
(N=xx) 
0.9 
mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 
mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total (N=xx) 
At Least 1 AE 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 Injection Site Reaction 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 TEAE [1] 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 Related TEAE [1] 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 Grade >=3 TEAE [1] 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 SAE 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 DLT 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
[1] Other than injection site reactions. 
Note: At least 1 = Any. AE = Adverse Event. TEAE = Treatment-Emergent Adverse Event. SAE = Serious Adverse Event. DLT = Dose Limiting 
Toxicity. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
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Statistical Analysis Plan 
 
Page 74 of 142 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.1.2 
 
Incidence of Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term (ITT/Safety Population) 
 
MedDRA SOC / Preferred Term 
Sta-
tistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 
mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
At Least 1 TEAE 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 2 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 3 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Etc. 
 
 
 
 
 
 
 
 
Note: TEAE = Treatment-Emergent Adverse Event. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
 
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Page 75 of 142 
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Page 1 of y 
Protocol 8400-401 
Table 14.3.1.3 
 
Incidence of Treatment-Emergent Adverse Events by Relationship to Study Drug and by MedDRA System Organ Class and Preferred Term 
(ITT/Safety Population) 
 
 
 
0.6 mg/kg/wk (N=xx) 
 
0.9 mg/kg/wk (N=xx) 
 
1.2 mg/kg/wk (N=xx) 
MedDRA SOC /  
Preferred Term 
Sta-
tistic 
Drug-Related 
Not Drug-
Related 
 
Drug-
Related 
Not Drug-
Related 
 
Drug-
Related 
Not Drug-
Related 
At Least 1 TEAE 
n (%) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Etc. 
 
 
 
 
 
 
 
 
 
Note: TEAE = Treatment-Emergent Adverse Event. Drug related adverse events are those which are identified by the investigator as 
probably or possibly related to the study drug and not related adverse events are those which are unlikely and not related to the 
study drug. The most related occurrence is counted if the patient experienced multiple occurrences of the same adverse event. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Move onto 2 pages as needed; include all dose groups and total (0.6, 0.9, 1.2, 1.8, 2.4, and total), see following 
page.  
 
 
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Statistical Analysis Plan 
 
Page 76 of 142 
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Page 2 of y 
Protocol 8400-401 
Table 14.3.1.3 
 
Incidence of Treatment-Emergent Adverse Events by Relationship to Study Drug and by MedDRA System Organ Class and Preferred Term 
(ITT/Safety Population) 
 
 
 
1.8 mg/kg/wk (N=xx) 
 
2.4 mg/kg/wk (N=xx) 
 
Total (N=xx) 
MedDRA SOC /  
Preferred Term 
Sta-
tistic 
Drug-Related 
Not Drug-
Related 
 
Drug-
Related 
Not Drug-
Related 
 
Drug-
Related 
Not Drug-
Related 
At Least 1 TEAE 
n (%) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Etc. 
 
 
 
 
 
 
 
 
 
Note: TEAE = Treatment-Emergent Adverse Event. Drug related adverse events are those which are identified by the investigator as 
probably or possibly related to the study drug and not related adverse events are those which are unlikely and not related to the 
study drug. The most related occurrence is counted if the patient experienced multiple occurrences of the same adverse event. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
  
 
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Statistical Analysis Plan 
 
Page 77 of 142 
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Page x of y 
Protocol 8400-401 
Table 14.3.1.4 
 
Incidence of Non-Serious Adverse Events, by MedDRA System Organ Class and Preferred Term (Safety Population) 
 
MedDRA SOC / Preferred Term 
Statistic 
0.6 mpk 
(N=xx) 
0.9 mpk 
(N=xx) 
1.2 mpk 
(N=xx) 
1.8 mpk 
(N=xx) 
2.4 mpk 
(N=xx) 
Total 
(N=xx) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
N (%) 
N (%) 
N (%) 
N (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 2 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
N (%) 
N (%) 
N (%) 
N (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Etc. 
 
 
 
 
 
 
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
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Statistical Analysis Plan 
 
Page 78 of 142 
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Page 1 of y 
Protocol 8400-401 
Table 14.3.1.5 
 
Incidence of Treatment-Emergent Adverse Events by Intensity and by MedDRA System Organ Class and Preferred Term 
(ITT/Safety Population) 
 
 
 
0.6 mg/kg/wk (N=xx) 
 
0.9 mg/kg/wk (N=xx) 
 
1.2 mg/kg/wk (N=xx) 
MedDRA SOC /  
Preferred Term 
Sta-
tistic 
Grade 1 or 
2 
Grade >= 
3 
Total 
 
Grade 1 
or 2 
Grade >= 
3 
Total 
 
Grade 1 
or 2 
Grade >= 
3 
Total 
At Least 1 TEAE 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TEAE = Treatment-Emergent Adverse Event. The highest intensity occurrence is counted if the patient experienced multiple 
occurrences of the same adverse event. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Move onto 2 pages as needed; include all dose groups and total (0.6, 0.9, 1.2, 1.8, 2.4, and total), see following 
page.  
 
 
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Statistical Analysis Plan 
 
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Confidential 
Page 2 of y 
Protocol 8400-401 
Table 14.3.1.5 
 
Incidence of Treatment-Emergent Adverse Events by Intensity and by MedDRA System Organ Class and Preferred Term 
(ITT/Safety Population) 
 
 
 
1.8 mg/kg/wk (N=xx) 
 
2.4 mg/kg/wk (N=xx) 
 
Total (N=xx) 
MedDRA SOC /  
Preferred Term 
Sta-
tistic 
Grade 1 or 
2 
Grade >= 
3 
Total 
 
Grade 1 
or 2 
Grade >= 
3 
Total 
 
Grade 1 
or 2 
Grade >= 
3 
Total 
At Least 1 TEAE 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TEAE = Treatment-Emergent Adverse Event. The highest intensity occurrence is counted if the patient experienced multiple 
occurrences of the same adverse event. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
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Statistical Analysis Plan 
 
Page 80 of 142 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.1.6 
 
Incidence of Dose-Limiting Toxicity Adverse Events by MedDRA System Organ Class and Preferred Term (ITT/Safety Population) 
 
MedDRA SOC / Preferred Term 
Statistic 
0.6 
mg/kg/wk 
(N=xx) 
0.9 
mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 
mg/kg/wk 
(N=xx) 
2.4 
mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
At Least 1 DLT 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 2 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: DLT = Dose-Limiting Toxicity. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
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Statistical Analysis Plan 
 
Page 81 of 142 
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13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.1.7 
 
Incidence of Local Injection Site Reactions Worst Grade Post Baseline (ITT/Safety Population) 
 
Symptom / 
Toxicity Grade 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
Pain 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Tenderness 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
<Repeat above format for Pruritus and Induration> 
Blister 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Blister (mm) 
 
n 
Mean (SD) 
Median 
Min,Max 
25th Percentile 
75th Percentile 
90th Percentile 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
<Repeat above format (2 rows each) for Ulceration and Necrosis> 
Note: In the case of multiple grades, only the worst grade post baseline is counted for each subject and symptom regardless of the 
site of injection. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
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Statistical Analysis Plan 
 
Page 82 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.1.8 
 
Incidence of Local Injection Site Reactions Worst Grade by Visit (ITT/Safety Population) 
 
Visit 
Symptom / 
Toxicity Grade 
Statistic 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
Day 1 
Pain 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Tenderness 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Etc. 
 
 
 
 
 
 
 
Day 3 
Pain 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Tenderness 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Etc. 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
Note: In the case of multiple grades, only the worst grade at each visit is counted for each subject and symptom regardless of the 
site of injection. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Include all symptoms and all visits.  
 
 
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Statistical Analysis Plan 
 
Page 83 of 142 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.2.1 
 
Listing of Deaths 
 
 
 
 
Onset 
 
End 
 
 
Dose 
Group 
Patient 
Number 
SOC 
Preferred 
Term 
Date/Time 
Rel 
Day 
[1]  Date/Time 
Rel 
Day 
[1] 
Sever-
ity [2] 
Serious 
Rela-
tionship 
[3] 
Action 
Taken with 
IMO-8400 
Action 
Taken 
for AE 
Sequelae 
at 
Resolution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Yes 
No 
 
 
 
Yes 
No 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] 1 = Grade 1: Mild. 2 = Grade 2: Moderate. 3 = Grade 3: Marked. 4 = Grade 4: Extreme. 5 = Grade 5: Death. 
[3] Relationship to Study Drug: Prob Rel = Probably Related, Poss Rel = Possibly Related, Unlike Rel = Unlikely Related, Not Rel = Not 
related. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If sequelae at resolution, concatenate specifics (Yes: Specify sequelae). 
 
 
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Statistical Analysis Plan 
 
Page 84 of 142 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.2.2 
 
Listing of Serious Adverse Events 
 
 
 
 
Onset 
 
End 
 
Dose 
Group 
Patient 
Number 
SOC 
Preferred 
Term 
Date/
Time 
Rel 
Day 
[1] 
 
Date/T
ime 
Rel 
Day 
[1] 
Sever-
ity [2] 
Rela-
tionship 
[3] 
Action 
Taken 
with 
IMO-8400 
Action 
Taken 
for AE 
Sequelae at 
Resolution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
No 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] 1 = Grade 1: Mild. 2 = Grade 2: Moderate. 3 = Grade 3: Marked. 4 = Grade 4: Extreme. 5 = Grade 5: Death. 
[3] Relationship to Study Drug: Prob Rel = Probably Related, Poss Rel = Possibly Related, Unlike Rel = Unlikely Related, Not Rel = Not 
related. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If sequelae at resolution, concatenate specifics (Yes: Specify sequelae). 
 
 
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Confidential and Proprietary 
84-289


Statistical Analysis Plan 
 
Page 85 of 142 
Protocol 8400-401, Final Version 1.0 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.2.3 
 
Listing of Treatment Discontinuations Due to Adverse Events 
 
 
 
 
Onset 
 
End 
 
 
Dose 
Group 
Patient 
Number 
SOC 
Preferred 
Term 
Date/
Time 
Rel 
Day 
[1] 
 
Date/
Time 
Rel 
Day 
[1] 
Sever-
ity [2] 
Serious 
Rela-
tionship 
[3] 
Action 
Taken 
with 
IMO-8400 
Action 
Taken 
for AE 
Sequelae at 
Resolution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
No 
 
 
 
Yes 
No 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] 1 = Grade 1: Mild. 2 = Grade 2: Moderate. 3 = Grade 3: Marked. 4 = Grade 4: Extreme. 5 = Grade 5: Death. 
[3] Relationship to Study Drug: Prob Rel = Probably Related, Poss Rel = Possibly Related, Unlike Rel = Unlikely Related, Not Rel = Not 
related. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If sequelae at resolution, concatenate specifics (Yes: Specify sequelae). 
  
 
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Confidential and Proprietary 
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Statistical Analysis Plan 
 
Page 86 of 142 
Protocol 8400-401, Final Version 1.0 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.4.1 
 
Listing of Clinically Significant Abnormal Laboratory Values (ITT/ Safety Population) 
 
 
 
 
 
 
 
 
Normal Range 
 
Dose 
Group 
Patient 
Number 
Date of 
Collection 
Rel Day 
[1] 
Lab Test 
Results 
Unit 
Lower 
Limit 
Upper 
Limit 
CTCAE Grade 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: LP - Low Panic, L - Low Normal, H - High Normal, HP - High Panic, AB – Abnormal.  
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
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Statistical Analysis Plan 
 
Page 87 of 142 
Protocol 8400-401, Final Version 1.0 
13 January 2015 
 
 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.5.1 
 
Study Drug Exposure (ITT/Safety Population) 
 
Parameter 
Statistics 
0.6 mg/kg/wk 
(N=xx) 
0.9 mg/kg/wk 
(N=xx) 
1.2 mg/kg/wk 
(N=xx) 
1.8 mg/kg/wk 
(N=xx) 
2.4 mg/kg/wk 
(N=xx) 
Total  
(N=xx) 
Cumulative dose [1] 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Cycles Received 
 
Received 1 cycle 
 
Received 2 cycles 
 
Received 3 cycles 
 
Received 4 cycles 
 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number missed doses 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Reason dose missed 
 
DLT 
 
AE 
 
Visit missed 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
[1] Cumulative dose is the dose injected multiplied times the number of injections. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Repeat for: 
Table 14.3.5.2  Study Drug Exposure (PP Population) 
 
 
 
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Statistical Analysis Plan 
 
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Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.3.5.3 
 
Summary and Change from Baseline for Hematology Parameters by Time Point and Dose Group (ITT/Safety Population) 
 
 
0.6 mg/kg/wk (N=xx) 
0.9 mg/kg/wk (N=xx) 
1.2 mg/kg/wk (N=xx) 
Laboratory 
Parameter 
Visit 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Lab Test 1 
(unit) 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
C1W2 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Etc.  
 
 
 
  
 
  
 
Lab Test 2 
(unit) 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
C1W2 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Etc.  
 
 
 
  
 
  
 
Note: Baseline = the most recent laboratory assessments before the first dose of study medication. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Repeat analyses for all laboratory parameters. Move onto 2 pages as needed; include all dose groups and total (0.6, 
0.9, 1.2, 1.8, 2.4, and total), see following page. For the Box plot figures, include standard deviation as error bars. 
 
Figure:  
Figure 14.3.5.3  Summary and Change from Baseline for Hematology Parameters by Time Point and Dose Group - Box Plot 
(ITT/Safety Population) 
 
Repeat for: 
Table 14.3.5.4  Summary and Change from Baseline for Chemistry Parameters by Time Point and Dose Group (ITT/Safety Population) 
Figure 14.3.5.4  Summary and Change from Baseline for Chemistry Parameters by Time Point and Dose Group - Box Plot (ITT/Safety 
Population) 
Table 14.3.5.5  Summary and Change from Baseline for Coagulation Parameters by Time Point and Dose Group (ITT/Safety Population) 
Figure 14.3.5.5  Summary and Change from Baseline for Coagulation Parameters by Time Point and Dose Group - Box Plot (ITT/Safety 
Population) 
 
 
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Statistical Analysis Plan 
 
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Confidential 
Page 2 of y 
Protocol 8400-401 
Table 14.3.5.3 
 
Summary and Change from Baseline for Hematology Parameters by Time Point and Dose Group (ITT/Safety Population) 
 
 
1.8 mg/kg/wk (N=xx) 
2.4 mg/kg/wk (N=xx) 
Total (N=xx) 
Laboratory 
Parameter 
Visit 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Lab Test 1 
(unit) 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
C1W2 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Etc.  
 
 
 
  
 
  
 
Lab Test 2 
(unit) 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
C1W2 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Etc.  
 
 
 
  
 
  
 
Etc.  
 
 
 
 
  
 
  
 
Note: Baseline = the most recent laboratory assessments before the first dose of study medication. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
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Page x of y 
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Table 14.3.5.6A 
 
Shifts from Baseline to Worst CTC Grade Post-Baseline in Hematology Parameters by Dose Group (ITT/Safety Population) 
 
 
Worst CTC Grade Post-Baseline Results 
Laboratory 
Parameter 
Dose Group 
Baseline 
Results 
Sta-
tistic 
WNL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Missing 
Lab Test 1 
(unit) 
0.6 mg/kg/wk 
WNL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Missing 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
0.9 mg/kg/wk 
WNL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Missing 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Etc. 
 
 
 
 
 
 
 
 
Lab Test 2 
(unit) 
0.6 mg/kg/wk 
WNL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Missing 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Etc. 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
Note: Baseline = the most recent laboratory assessments before the first dose of study medication. WNL = Within Normal Limit. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Repeat analyses for all laboratory parameters and all visits. Include all dose groups and total (0.6, 0.9, 1.2, 1.8, 
2.4, and total). 
 
Repeat for: 
Table 14.3.5.6B  Shifts from Baseline to Worst CTC Grade Post-Baseline in Chemistry Parameters by Dose Group (ITT/Safety Population) 
Table 14.3.5.6C  Shifts from Baseline to Worst CTC Grade Post-Baseline in Coagulation Parameters by Dose Group 
(ITT/Safety Population) 
 
 
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Table 14.3.5.7 
 
Summary and Change from Baseline for Vital Signs by Time Point and Dose Group (ITT/Safety Population) 
 
 
0.6 mg/kg/wk (N=xx) 
0.9 mg/kg/wk (N=xx) 
1.2 (N=xx) 
Parameter 
Visit 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Temperature 
(ºC) 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
C1W2 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Etc.  
 
 
 
  
 
  
 
Etc.  
 
 
 
 
  
 
  
 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Repeat analyses for all vital sign parameters. Move onto 2 pages as needed; include all dose groups and total (0.6, 
0.9, 1.2, 1.8, 2.4, and total). For the Box plot figures, include standard deviation as error bars. 
 
Figure:  
   Figure 14.3.5.7 - Summary and Change from Baseline for Vital Signs by Time Point and Dose Group - Box Plot (ITT/Safety Population) 
 
 
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Table 14.3.5.7 
 
Summary and Change from Baseline for Vital Signs by Time Point and Dose Group (ITT/Safety Population) 
 
 
1.8 mg/kg/wk (N=xx) 
2.4 mg/kg/wk (N=xx) 
Total (N=xx) 
Parameter 
Visit 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Temperature 
(ºC) 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
C1W2 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Etc.  
 
 
 
  
 
  
 
Etc.  
 
 
 
 
  
 
  
 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
  
 
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Page 93 of 142 
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Page 1 of y 
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Table 14.3.5.8 
 
Summary and Change from Baseline for Electrocardiogram Results by Time Point and Dose Group (ITT/Safety Population) 
 
 
0.6 mg/kg/wk (N=xx) 
0.9 mg/kg/wk (N=xx) 
1.2 (N=xx) 
ECG 
Parameter 
Visit 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
HR (bpm) 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
C1W2 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Etc.  
 
 
 
  
 
  
 
Etc.  
 
 
 
 
  
 
  
 
 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Repeat analyses for all vital sign parameters. Move onto 2 pages as needed; include all dose groups and total (0.6, 
0.9, 1.2, 1.8, 2.4, and total).  
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Page 2 of y 
Protocol 8400-401 
Table 14.3.5.8 
 
Summary and Change from Baseline for Electrocardiogram Results by Time Point and Dose Group (ITT/Safety Population) 
 
 
1.8 mg/kg/wk (N=xx) 
2.4 mg/kg/wk (N=xx) 
Total (N=xx) 
ECG 
Parameter 
Visit 
Statistic 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
Actual 
Change from 
Baseline 
HR (bpm) 
Baseline 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
-- 
 
C1W2 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
Etc.  
 
 
 
  
 
  
 
Etc.  
 
 
 
 
  
 
  
 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Repeat analyses for all vital sign parameters. Move onto 2 pages as needed; include all dose groups and total (0.6, 
0.9, 1.2, 1.8, 2.4, and total).  
 
 
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Page x of y 
Protocol 8400-401 
Table 14.3.5.9 
 
Listing of Abnormal Electrocardiogram Assessments (ITT/Safety Population) 
 
Dose 
Group 
Patient 
Number 
Date/Time of 
Assessment 
Rel 
Day 
[1] 
Ventricular 
Rate (bpm) 
RR Interval 
(msec) 
PR 
Interval 
(msec) 
QRS 
Interval 
(msec) 
QT 
Interval 
(msec) 
QTc 
Interval 
(msec)  
QTc 
Interval 
Method 
ECG 
Result 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Include where ECG Result = “Abnormal, Not clinically significant” or “Abnormal, clinically significant”. 
 
 
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Page x of y 
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Table 14.3.5.10 
 
Concomitant Medications (ITT/Safety Population) 
 
ATC Classification 
Statistic 
0.6 
mg/kg/wk 
(N=xx) 
0.9 
mg/kg/wk 
(N=xx) 
1.2  
mg/kg/wk 
(N=xx) 
1.8 
mg/kg/wk 
(N=xx) 
2.4 
mg/kg/wk 
(N=xx) 
Total 
(N=xx) 
Any Concomitant Medication 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
CM CLASS 1 
 
CM Code 1 
 
CM Code 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
CM CLASS 2 
 
CM Code 1 
 
CM Code 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Etc. 
 
 
 
 
 
 
 
Reference Listing: 16.x.x.x 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Repeat analyses for all CM classes and CM codes.  
  
 
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Statistical Analysis Plan 
 
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8.3. 
Data Listing Shells 
The following data listings will be produced. 
 
 
 
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Statistical Analysis Plan 
 
Page 98 of 142 
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Page x of y 
Protocol 8400-401 
Listing 16.0.1 
 
System Organ Class Abbreviations 
 
SOC 
Abbreviations 
Blood and lymphatic system disorders 
BLOOD 
Cardiac disorders 
CARD 
Congenital, familial and genetic disorders 
CONGN 
Ear and labyrinth disorders 
EAR 
Endocrine disorders 
ENDO 
Eye disorders 
EYE 
Gastrointestinal disorders 
GASTR 
General disorders and administration site conditions 
GENRL 
Hepatobiliary disorders 
HEPAT 
Immune system disorders 
IMMUN 
Infections and infestations 
INFCT 
Injury, poisoning and procedural complications 
INJUR 
Investigations 
INVST 
Metabolism and nutrition disorders 
METAB 
Musculoskeletal and connective tissue disorders 
MUSCL 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
NEOPL 
Nervous system disorders 
NERV 
Pregnancy, puerperium and perinatal conditions 
PREG 
Psychiatric disorders 
PSYCH 
Renal and urinary disorders 
RENAL 
Reproductive system and breast disorders 
REPRO 
Respiratory, thoracic and mediastinal disorders 
RESP 
Skin and subcutaneous tissue disorders 
SKIN 
Social circumstances 
SOCL 
Surgical and medical procedures 
SURG 
Vascular disorders 
VASC 
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: Verify the list of abbreviations includes all SOCs.  
 
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Statistical Analysis Plan 
 
Page 99 of 142 
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Page x of y 
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Listing 16.2.1.1 
 
Patients Discontinuing Treatment Prematurely 
 
Dose 
Group 
Patient 
Number 
Number of  
Cycles 
Received 
Date of 
Last Dose 
Rel Day 
[1] 
Reason Discontinued 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: Reason discontinued taken from “Please indicate the primary reason patient did not complete all weeks” question.  
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Statistical Analysis Plan 
 
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Listing 16.2.1.2 
 
End of Treatment (EOT) Visit Status 
 
Dose 
Group 
Patient 
Number 
Date of 
Treatment 
Termination 
Rel 
Day 
[1] 
Primary Reason for 
Termination of 
Treatment 
Specifics 
Comments 
Date of 
EOT 
visit 
Rel 
Day 
[1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLT event 
Disease 
Progression 
Completion of 24 
weeks treatment 
AE 
Withdrawal of 
Consent 
Lost to Follow-Up 
Study Termination 
by Sponsor 
Other 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: Primary reason for termination of treatment taken from the EOT page.  Include additional specification under 
“Specifics”. Include “Please specify DLT event”, “Please specify disease progression”, “Please specify other adverse event”, “Please 
explain all attempts to contact the subject”, and “Please specify other”.  
 
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Statistical Analysis Plan 
 
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Listing 16.2.1.3 
 
End of Study (EOS) Visit Status 
 
Dose 
Group 
Patient 
Number 
Date of 
Visit 
Rel 
Day 
[1] 
Reason 
Visit Not 
Completed 
Date of 
Death 
Rel 
Day 
[1] 
Cause of 
Death 
Date 
Last 
Seen  
Rel 
Day 
[1] 
Completed 
24 Weeks 
of Study 
Treatment  
Primary Reason 
Patient did not 
Complete 24 Weeks 
Comments 
 
 
 
 
 
 
 
Death 
Lost to 
Follow-up 
Withdrawal 
of Consent 
 
 
 
 
 
 
Yes 
No 
Disease 
Progression 
AE related to 
study treatment 
AE not related to 
study treatment 
Pregnancy 
Lost to Follow-up 
Withdrawal of 
Consent  
Physician Decision 
Study terminated 
by Sponsor 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
 
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Listing 16.2.2.1 
 
Inclusion Criteria 
 
Criterion 
Number 
Inclusion Criteria 
IN-1 
Be at least 18 years of age. 
IN-2 
Have signed the current approved informed consent form. 
IN-3 
For women of childbearing potential and men, agree to use effective contraceptive methods from screening, through 
the study, and for at least 4 weeks after the last dose of study drug. 
IN-4 
For women of childbearing potential, have a negative serum pregnancy test at screening. 
IN-5 
Be willing and able to comply with this protocol. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
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Listing 16.2.2.2 
 
Exclusion Criteria 
 
Criterion 
Number 
Exclusion Criteria 
EX-1 
Has known hypersensitivity to any oligodeoxynucleotide. 
EX-2 
Is nursing. 
EX-3 
Has body weight <50 kg. 
EX-4 
Has BMI >34.9 kg/m2. 
EX-5 
Has an indeterminate or positive test for antibody to human immunodeficiency virus (HIV-1 or -2) or hepatitis C 
virus (HCV). 
EX-6 
Has a positive test for hepatitis B surface antigen (HBsAg). 
EX-7 
Has, at screening, safety laboratory tests meeting one or more of the following criteria: 
– Hemoglobin <7.5 g/dL 
– Serum creatinine >2.5x ULN 
EX-8 
Has, at screening, any other safety laboratory tests that are Grade 2 or higher based on NCI CTCAE criteria. 
EX-9 
Is, at the initiation of study drug, receiving chronic systemic corticosteroid therapy >20 mg of prednisone daily 
(or equivalent); steroids administered topically or by inhalation are permitted. 
EX-10 
Has, at the initiation of study drug, received cytotoxic chemotherapy within the past three (3) weeks or rituximab 
within the past two (2) months; for other anti-cancer therapies (approved or investigational) the interval will be 
determined in consultation with the Medical Monitor. 
EX-11 
Has, at the initiation of study drug, an active infection requiring systemic antibiotics. 
EX-12 
Has had within the 4 weeks prior to initiation of study drug, or is expected to have during the study period, 
surgery requiring general anesthesia. 
EX-13 
Has active autoimmune cytopenia (anemia, thrombocytopenia, leukopenia) requiring concomitant therapy. 
EX-14 
Has life expectancy of less than 3 months. 
EX-15 
Has performance status of Grade 3 or 4 (Eastern Cooperative Oncology Group [ECOG] criteria). 
EX-16 
Has heart failure of Class III or IV (New York Heart Association criteria). 
EX-17 
Has sensory or motor neuropathy of Grade 4 (NCI CTCAE v4.03 criteria). 
EX-18 
Has other significant medical conditions (chronic or active within the past 6 months), including, but not limited 
to: cardiac disease (e.g., unstable angina, myocardial infarction, ventricular arrhythmia); uncontrolled seizure 
disorder; liver disease; or uncontrolled diabetes. 
EX-19 
Has any other condition that would, in the opinion of the Investigator, potentially compromise the safety or 
compliance of the patient or may preclude the patient’s successful completion of the clinical trial. 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
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Statistical Analysis Plan 
 
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Listing 16.2.2.3 
 
Listing of Inclusion/Exclusion Criteria Not Met  
 
Dose 
Group 
Patient 
Number 
IN/EX Criteria  
Not Met 
Waiver 
Granted 
Waiver 
Details 
Comments 
 
 
 
Yes 
No 
 
 
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
 
 
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Statistical Analysis Plan 
 
Page 105 of 142 
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Listing 16.2.2.4 
 
Intent–To-Treat Patients Excluded from Per-Protocol Population 
 
Dose  
Group 
Patient  
Number 
Reason for Exclusion 
 
 
 
 
 
 
 
 
 
 
 
Note: This listing presents only subjects who are removed from the per-protocol population. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
  
 
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Statistical Analysis Plan 
 
Page 106 of 142 
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Listing 16.2.3 
 
Protocol Deviations 
 
Dose  
Group 
Patient  
Number 
Date of 
Deviation 
Rel 
Day 
[1] 
Category of Deviation 
Deviation Specifics 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion Criteria Not 
Met 
Prohibited Medication Taken 
Blood Specimen Collection Missed / 
Out of  Window 
Other Protocol Procedure Missed / 
Out of Window 
IMO-8400 Dose Missed 
Other 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
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Statistical Analysis Plan 
 
Page 107 of 142 
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Listing 16.2.4.1 
 
Demographic Characteristics 
 
Dose Group 
Patient 
Number 
Informed 
Consent 
Date  
Protocol 
Version 
Date 
Date of 
Birth 
Age 
(Years) 
Gender 
Of Child-
bearing 
Potential 
Race 
Ethnicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Male 
Female 
Yes 
No 
American Indian or 
Alaska Native 
Asian 
Black 
Native Hawaiian or 
Other Pacific Islander 
White 
Other 
Hispanic or 
Latino 
Not Hispanic 
or Latino" 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: Concatenate specifics if “other” is chosen for race (Other: Specify).  
 
 
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Statistical Analysis Plan 
 
Page 108 of 142 
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Page x of y 
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Listing 16.2.4.2 
 
Medical History 
 
 
Dose Group 
Patient 
Number 
System 
Disease/ Procedure 
Start Date 
End Date 
Ongoing at 
Screening? 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
No 
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: if Ongoing = Yes, mark ONGOING in end date column.  
 
 
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Statistical Analysis Plan 
 
Page 109 of 142 
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Page x of y 
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Listing 16.2.4.3A 
 
Waldenström’s Macroglobulinemia Disease History – Part 1 
 
Dose Group 
Patient 
Number 
Date of 
Diagnosis 
Date of first 
treatment for 
WM 
Experienced 
treatment-related 
AEs in past 3 months 
Subject has been 
hospitalized in 
the past year 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
No 
Yes 
No 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
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Statistical Analysis Plan 
 
Page 110 of 142 
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Listing 16.2.4.3B 
 
Waldenström’s Macroglobulinemia Disease History – Part 2 
 
 
 
 
AEs in the past 3 months 
 
Hospitalizations in the past year 
Dose 
Group 
Patient 
Number 
Experienced 
treatment-
related AEs in 
past 3 months 
Event Term Start Date 
End Date 
Subject has been 
hospitalized in 
the past year 
Date of 
Discharge 
Discharge Diagnosis 
 
 
 
 
 
 
 
 
 
 
Yes 
No 
 
 
 
Yes 
No 
 
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: if Ongoing = Yes, mark ONGOING in end date column.  
 
 
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Statistical Analysis Plan 
 
Page 111 of 142 
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Page x of y 
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Listing 16.2.4.4 
 
Prior Waldenström’s Macroglobulinemia Therapy 
 
Dose 
Group 
Patient 
Number 
Agent/ 
Treatment 
Start 
Date 
Stop 
Date 
Best Clinical 
Response 
Reason for 
Discontinuation 
AEs experienced with this 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
 
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Statistical Analysis Plan 
 
Page 112 of 142 
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Page x of y 
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Listing 16.2.4.5 
 
MyD88 L265P Mutation Status 
 
Dose Group Patient Number 
MyD88 L265P Mutation Status  
 
 
Present 
Absent 
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: This data to come from an external source, and is not entered into the database.   
  
 
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Statistical Analysis Plan 
 
Page 113 of 142 
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Page x of y 
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Listing 16.2.5.1 
 
Study Drug Exposure 
 
Dose 
Group 
Patient 
Number 
Cycle  Week  
Both Doses 
Admin-
istered 
Injection 
Location 
Date/ 
Time  
Rel 
Day 
[1]  
Site 
 
Volume 
Dispensed 
(unit) 
Entire Dose 
Administered 
Cum-
ulative 
dose 
(mg) [2] 
 
 
 
 
 
 
Yes 
No 
First  
Second 
Site 
Home 
Visit 
 
 
 
 
Yes 
No: 
[Specify] 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] Cumulative dose is the volume dispensed multiplied times the number of injections. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: if Site = “Other”, concatenate specifics, “Other Injection Site” 
Programming note: If entire dose not administered, concatenate specifics “Please explain why entire dose was not administered.” 
 
 
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Statistical Analysis Plan 
 
Page 114 of 142 
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Page x of y 
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Listing 16.2.5.2 
 
Pharmacokinetic Concentrations 
 
Dose 
Group 
Patient 
Number 
Collection 
Date  
Rel Day 
[1] 
Time Point 
Collection 
Time 
Relative 
Time [2] 
Drug Concentration (unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] Relative time is calculated with respect to the time of each dose.  
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
 
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Statistical Analysis Plan 
 
Page 115 of 142 
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Page x of y 
Protocol 8400-401 
Listing 16.2.5.3 
 
Pharmacokinetic Parameters 
 
 
 
 
 
 
Parameter 
Dose 
Group 
Patient 
Number 
Collection 
Date  
Rel 
Day 
[1] 
Time Point 
Maximum 
Conc. 
(mg/ml)   
Time to 
Maximum 
Conc. (hr)    
AUC last 
(hr*mg/mL)  
AUC Infinity 
(hr*mg/ml)       RA (AUC) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] Relative time is calculated with respect to the time of each dose.  
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
  
 
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Statistical Analysis Plan 
 
Page 116 of 142 
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Page x of y 
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Listing 16.2.6.1 
 
Disease Response  
 
Dose 
Group 
Patient 
Number 
Date of 
Assessment 
Rel 
Day 
[1] 
Parameter 
Clinical Response  
Comments 
Overall 
Response [2] 
 
Serum Monoclonal IgM 
Bone Marrow Histology 
Adenopathy 
Organomegaly 
Cytopenias 
Symptoms 
CR 
VGPR 
PR 
MR 
SD 
PD 
NE 
Delayed Response 
NA 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] Overall Response derived from data entered onto the Disease Assessment eCRF based on the VIth International Workshop on 
Waldenström’s Macroglobulinemia (Owen et al, 2012). 
Note: CR = Complete response. VGPR = Very good partial response. PR = Partial response. MR = Minor response. SD = Stable disease. PD = 
Progressive disease. NE = Not evaluable. NA = Not applicable.  
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: Overall Response retrieved from external data source, Excel spreadsheet from Idera.  
 
 
 
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Statistical Analysis Plan 
 
Page 117 of 142 
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Page x of y 
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Listing 16.2.6.2A 
 
Disease Assessment – Part 1 
 
 
 
 
 
 
Physical assessment of lymphadenopathy 
 
Physical assessment of hepatomegaly 
Dose 
Group 
Patient 
Number 
Clinical 
Assessments 
Completed 
Date of 
Assessment 
Rel 
Day 
[1] 
Results 
Region 
Size 
(unit) 
Tenderness 
 
Results 
Abnormality 
Clinically 
Significant 
Yes 
No 
 
Normal  
Abnormal 
Not Done 
 
 
None 
Mild 
Moderate 
Severe 
 
Normal  
Abnormal 
Not Done 
 
Yes 
No 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
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Statistical Analysis Plan 
 
Page 118 of 142 
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Page x of y 
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Listing 16.2.6.2B 
 
Disease Assessment – Part 2 
 
 
 
 
 
 
Physical assessment of splenomegaly 
Dose 
Group 
Patient 
Number 
Clinical 
Assessments 
Completed 
Date of 
Assessment 
Rel 
Day 
[1] 
Results 
Enlarged 
Palpable 
Tenderness 
Yes 
No 
 
Normal  
Abnormal 
Not Done 
Yes 
No 
Yes 
No 
None 
Mild 
Moderate 
Severe 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
  
 
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Statistical Analysis Plan 
 
Page 119 of 142 
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Page x of y 
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Listing 16.2.7.1 
 
Adverse Events by Patient and MedDRA System Organ Class / Preferred Term 
 
Dose Group:  
 
 
 
Onset 
 
End 
 
 
Patient 
Number 
SOC 
Preferred 
Term 
Date/
Time 
Rel 
Day 
[1] 
 
Date/
Time 
Rel 
Day 
[1] 
Sever-
ity [2] 
Serious 
Rela-
tionship 
[3] 
Action 
Taken with 
IMO-8400 
Action 
Taken 
for AE 
Sequelae at 
Resolution 
 
 
 
 
 
 
 
 
 
Yes 
No 
 
 
 
Yes 
No 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] 1 = Grade 1: Mild. 2 = Grade 2: Moderate. 3 = Grade 3: Marked. 4 = Grade 4: Extreme. 5 = Grade 5: Death. 
[3] Relationship to Study Drug: Prob Rel = Probably Related, Poss Rel = Possibly Related, Unlike Rel = Unlikely Related, Not Rel = Not 
related. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If sequelae at resolution, concatenate specifics (Yes: Specify sequelae). 
 
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Statistical Analysis Plan 
 
Page 120 of 142 
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Listing 16.2.7.2 
 
Adverse Events by MedDRA System Organ Class and Preferred Term 
 
 
 
System Organ Class:  
 
 
 
Onset 
 
End 
 
 
Preferred 
Term  
Dose 
Group 
Patient 
Number 
Date/
Time 
Rel 
Day 
[1] 
 
Date/
Time 
Rel 
Day 
[1] 
Sever-
ity [2] 
Serious 
Rela-
tionship 
[3] 
Action 
Taken with 
IMO-8400 
Action 
Taken 
for AE 
Sequelae at 
Resolution 
 
 
 
 
 
 
 
 
 
Yes 
No 
 
 
 
Yes 
No 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] 1 = Grade 1: Mild. 2 = Grade 2: Moderate. 3 = Grade 3: Marked. 4 = Grade 4: Extreme. 5 = Grade 5: Death. 
[3] Relationship to Study Drug: Prob Rel = Probably Related, Poss Rel = Possibly Related, Unlike Rel = Unlikely Related, Not Rel = Not 
related. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If sequelae at resolution, concatenate specifics (Yes: Specify sequelae). 
 
 
 
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Statistical Analysis Plan 
 
Page 121 of 142 
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Page x of y 
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Listing 16.2.7.3 
 
Glossary of Adverse Event Verbatim Terms by MedDRA System Organ Class, Preferred Term, and Patient 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Note: Sort the listing by SOC, PT, Verbatim, Dose Group, and Patient Number. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
  
 
MedDRA 
 
 
 
SOC 
Preferred Term 
Dose Group 
Patient Number 
Investigator Reported Term 
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Statistical Analysis Plan 
 
Page 122 of 142 
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Listing 16.2.7.4 
 
Injection Site Reaction Assessments  
 
 
 
 
 
 
 
 
 
Dose 
Group 
Patient 
Number 
Visit of 
Assessment 
Date of 
Assessment 
Rel 
day 
[1] 
Time of 
Assessment  
Visit of 
Injection 
Site of 
Injection 
Any ISR Reported  
 
 
 
 
 
 
 
 
Yes 
No 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: If there was no injection site reaction noted, then further data was not recorded. 
      Ery=Erythema, Ind=Induration, Tend=Tenderness, Prur=Pruritus. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: Put the definitions of the severity gradation on the first page. 
 
 
 
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Statistical Analysis Plan 
 
Page 123 of 142 
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Listing 16.2.7.5 
 
Patient Reported Injection Site Reactions  
 
Dose 
Group 
Patient 
Number 
Date of 
Assessment 
Rel 
Day 
[1] Trait 
Date of 
Onset 
Rel 
day 
[1] 
Date of 
Resolution 
Rel 
Day 
[1] 
Severity 
Reaction 
ongoing at 
time of 
assessment 
Sequelae 
ISR 
Treated 
 
 
 
 
 
 
 
 
 
 
Yes 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If ISR treated, concatenate specifics for con med or other treatment.  
 
 
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Statistical Analysis Plan 
 
Page 124 of 142 
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Page x of y 
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Listing 16.2.7.6 
 
Observed Injection Site Reactions  
 
Dose 
Group 
Patient 
Number 
Date of 
Assessment 
Rel 
Day 
[1] Trait 
Status 
Severity 
Size 
(mm) 
ISR Treated 
Previous 
ISRs for 
same site 
Sequelae 
 
 
 
 
Erythema 
Induration 
Tenderness 
Pain 
Pruritus 
Blister 
Ulceration 
Necrosis 
Present 
Absent 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
NA 
 
 
Yes 
No 
Yes: Specify 
No  
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: NA = Not applicable 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If ISR treated, concatenate specifics for con med or other treatment. If sequelae = yes, concatenate specifics.  
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Statistical Analysis Plan 
 
Page 125 of 142 
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Confidential 
Page x of y 
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Listing 16.2.8.1A 
 
Laboratory Results: Hematology – Part 1 
Dose Group: [Description] 
 
Patient 
Number 
Date/Time of 
Collection 
Rel 
Day 
[1] 
WBC 
Count 
(unit) 
RBC 
Count 
(unit) 
Hemo-
globin 
(unit)  
HCT 
(unit) 
Platelet 
Count 
(unit) 
MCH 
(unit) 
MCHC 
(unit) 
MCV 
(unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: HCT = Hematocrit, RBCs = Red Blood Cells, MCH = Mean Corpuscular Hemoglobin, MCHC = Mean Corpuscular Hemoglobin Concentration,  
      MCV = Mean Corpuscular Volume, WBC = White Blood Cells. 
Note: LP - Low Panic, L - Low Normal, H - High Normal, HP - High Panic, AB – Abnormal.  
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: In all tables include SI parameters under the lab parameter. 
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Statistical Analysis Plan 
 
Page 126 of 142 
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Confidential 
Page x of y 
Protocol 8400-401 
Listing 16.2.8.1B 
 
Laboratory Results: Hematology – Part 2 
 
Dose Group: [Description] 
 
Patient 
Number 
Date/Time of 
Collection 
Rel 
Day 
[1] 
Neutro- 
phils 
(unit) 
Eosino- 
phils 
(unit) 
Baso- 
phils 
(unit) 
Lympho- 
cytes 
(unit) 
Mono- 
cytes 
(unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: LP - Low Panic, L - Low Normal, H - High Normal, HP - High Panic, AB – Abnormal. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: In all tables include SI parameters under the lab parameter. 
Programming Note: In all tables include SI parameters under the lab parameter. 
 
Repeat for: 
Listing 16.2.8.2  Laboratory Results: Chemistry 
Listing 16.2.8.3  Laboratory Results: Urinalysis 
Listing 16.2.8.4  Laboratory Results: Coagulation 
 
 
 
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Statistical Analysis Plan 
 
Page 127 of 142 
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Page x of y 
Protocol 8400-401 
Listing 16.2.8.5 
 
Laboratory Results: Serology 
 
Dose  
Group 
Patient 
Number 
Date/Time of 
Collection 
Rel 
Day 
[1] 
HBsAg 
HIV 
HCV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: HBsAg = Hepatitis B surface antigen, HIV = Human immuno deficiency virus, HCV = Hepatitis C virus. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
 
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Statistical Analysis Plan 
 
Page 128 of 142 
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Confidential 
Page x of y 
Protocol 8400-401 
Listing 16.2.8.6 
 
Urine Pregnancy Test Results 
 
Dose Group 
Patient Number 
Age 
Date/Time Sample Collected 
Rel Day [1] 
Result of Pregnancy Test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
  
 
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Statistical Analysis Plan 
 
Page 129 of 142 
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Confidential 
Page x of y 
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Listing 16.2.8.7 
 
Bone Marrow Biopsy 
 
Dose  
Group 
Patient 
Number 
Date Sample 
Collected 
Rel Day [1] 
HBsAg 
HIV 
HCV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: HBsAg = Hepatitis B surface antigen. HIV = Human immuno deficiency virus. HCV = Hepatitis C virus. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX  
 
 
 
 
DATE: DDMMMYYYY HH:MM 
  
 
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Serum Cytokines Test 
 
Dose Group 
Patient Number 
Date of 
Collection 
Rel Day 
[1] 
IL-6 (unit) 
IL-12 (unit) 
IL-17 (unit) 
IP-10 (unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
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Immunoglobulin (IgM) Results 
 
Dose Group 
Patient Number 
Date of 
Collection 
Rel Day 
[1] 
Monoclonal 
IgM (unit) 
Total IgM 
(unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
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Serum Antibody Results 
 
Dose Group 
Patient Number 
Visit 
Date of 
Collection 
Rel Day 
[1] 
Presence of 
Antibody to 
IMO-8400 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
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Vital Signs 
 
Dose 
Group 
Patient 
Number 
 
Date of 
Assessment 
Rel 
Day 
[1] 
 
Time-
point 
Height 
(cm) 
Weight 
(kg) 
SBP 
(mmHg) 
DBP 
(mmHg) 
Heart Rate 
(beats/min) 
Respiratory 
Rate 
(beats/min) 
Temperature 
(oC) 
Any 
Abnormal, CS 
Results? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: Clinically significant results are represented by ‘*’ after the result. 
 
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Physical Examination Findings 
 
Dose 
Group 
Patient 
Number 
Date of 
Assessment 
Rel Day 
[1] 
 
Timepoint 
Body System 
Findings 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
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Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
Dose 
Group 
Patient 
Number 
Visit 
ECOG Performance 
Status Assessed 
Date of 
Assessment 
Rel Day 
[1] 
ECOG Score 
 
 
 
 
 
 
 
 
 
Yes 
No 
 
 
  
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
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12-Lead Electrocardiogram Interval and Overall Assessment 
 
Dose Group:  
 
Patient 
Number 
Date/Time of 
Assessment 
Rel Day 
[1] 
Ventricular 
Rate (bpm) 
 
RR Interval 
(msec) 
PR 
Interval 
(msec) 
QRS 
Interval 
(msec) 
QT 
Interval 
(msec) 
QTc 
Interval 
(msec)  
QTc Interval 
Method 
ECG Result 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: If QT interval available, then QTc-Fridericia calculated. If not, then QTc Interval and Method taken from ECG Strip.  
ECG Result: NL = Normal; Ab-NCS = Abnormal, Not Clinically Significant; Ab-CS = Abnormal, Clinically Significant. 
 
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12-Lead Electrocardiogram – Comments on Abnormal Assessments  
 
Dose Group:  
 
Patient 
Number 
Date/Time of 
Assessment 
Rel Day 
[1] 
ECG Result 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
ECG Assessment: NL = Normal; Ab-NCS = Abnormal, Not Clinically Significant; Ab-CS = Abnormal, Clinically Significant. 
 
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Concomitant Medications 
 
Dose Group 
Patient 
Number 
Start Date/ 
Rel Day [1] 
End Date/ 
Rel Day [1] 
Medication 
Dose 
Unit 
Route 
Frequency 
Used 
to 
treat 
an AE 
AE 
# 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: BID = Twice a day, TID = Three times a day, QID = Four times a day, QD = Once a day, QOD = Every other day, QWK = Every week,    
      Q2WK = Once every 2 weeks, Q3WK = Once every 3 weeks, QH = Every hour, Q4H = Every 4 hours, Q6H = Every 6 hours,    
      OTO = One time only, PRN = As needed. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If medication is ongoing, enter ONGOING in end date column. If other is selected for unit, route, or frequency, 
concatenate specifics (Other: Specify).  
 
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9. 
REVISION HISTORY 
Not applicable; this is the first draft of the SAP. 
 
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10.
APPENDICES
10.1. 
Appendix 1: Evaluation of Response to Treatment and Disease
Status
Table 10-1 summarizes the criteria for response to treatment. The full text of the VIth 
International Workshop classification (Owen et al 2008) is provided below, in 
Section 10.2. 
Table 10-1  
Summary of Evaluation of Response to Treatment and Disease Status 
Parameter 
Response 
Stable 
Disease 
(SD) 
Progressive 
Disease (PD) 
Complete 
(CR) 
Very Good 
Partial 
(VGPR) 
Partial 
(PR) 
Minor 
(MR) 
Serum 
Monoclonal 
IgMa 
Absente 
≥90% 
reduction 
≥50% 
reduction 
≥25% to 
<50% 
reduction 
<25% 
reduction 
to 
<25% 
increase 
≥25% 
increase 
Bone Marrow 
histology 
Absence of 
malignant 
cells 
NA 
NA 
NA 
NA 
NA 
Adenopathy, 
Organomegalyb 
Resolved 
by CT 
Resolved 
by CT 
≥50% 
decrease 
by CT 
NA 
No 
progression 
Progression 
Cytopeniasc 
None 
None new 
None new 
None new 
None new 
Progression 
Symptomsd 
None 
None new 
None new 
None new 
None new 
Progression 
NA =Not applicable. 
a. Quantitative assessment by protein electrophoresis with immunofixation.
b. If present at baseline on CT.
c. Cytopenias: anemia, thrombocytopenia, leukopenia
d. Symptoms: unexplained recurrent fever ≥38.4°C, drenching night sweats, ≥10% weight loss, neuropathy,
symptomatic hyperviscosity, or symptomatic cryoglobulinemia. 
e. Must be confirmed ≥6 weeks later with a second serum immunofixation assay.
f. PD based on ≥25% increase in serum monoclonal IgM from nadir; must be confirmed by a second measurement.
The Third International Workshop for WM also defined the following categories (Kimby et al 2006). 
Not evaluable response: Reserved for situations in which there is insufficient data for a determination of 
response to treatment. 
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Delayed response: A delayed response is described particularly after treatment with purine analogue or 
monoclonal antibody. The recommendation was that patients should be followed for at least 12 weeks 
after treatment initiation to be considered unresponsive to therapy. 
 
 
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10.2. 
Appendix 2: Classification of Disease Response for Waldenström’s 
Macroglobulinemia 
Reproduced from Reference Owen et al 2008. 
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STATISTICAL ANALYSIS PLAN 
 
 
Phase 1/2 Open-label, Multiple-dose, Dose-escalation Study to Evaluate the 
Safety and Tolerability of IMO-8400 in Patients with Relapsed or 
Refractory Waldenström’s Macroglobulinemia 
 
Protocol Number: 
Protocol Version and Date: 
8400-401 
Version 7.0, 14 March 2016 
Version 6.0, 13 August 2015 
Version 5.0, 25 February 2015 
Version 4.0, 22 Sep 2014 
Version 3.0, 23 Jul 2014 
Version 2.0, 18 Nov 2013 
Version 1.0, 11 Oct 2013 
Name of Test Drug: 
IMO-8400 
Phase: 
Phase 1/2 
Methodology: 
Open-label, Multiple-dose, Dose-escalation, Multicenter 
Sponsor: 
Idera Pharmaceuticals, Inc. 
167 Sidney Street 
Cambridge, MA  02139 
Sponsor Representatives: 
Julie Brevard, MPH 
Director of Statistics 
Idera Pharmaceuticals, Inc. 
 
Mark Cornfeld, MD, MPH 
Vice President & Medical Lead, Oncology 
Idera Pharmaceuticals, Inc. 
Statistical Analysis Plan Date: 
21 April 2017 
Statistical Analysis Plan Version: 
Final Version 2.0 
 
 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Idera 
Pharmaceuticals, Inc. and any unauthorized use or disclosure of such information without the 
prior written authorization of Idera Pharmaceuticals, Inc. is expressly prohibited. 
 
 
 
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TABLE OF CONTENTS 
Section 
Page 
1.
Statistical Analysis Plan Objectives ............................................................................8
2.
Information From the Study Protocol.........................................................................9
2.1. 
Introduction and Objectives.............................................................................9 
2.1.1. 
Introduction ..........................................................................................9 
2.1.2. 
Study Objectives ..................................................................................9 
2.2. 
Study Design ....................................................................................................10 
2.2.1. 
Synopsis of Study Design ..................................................................10 
2.2.2. 
Stopping Rules ...................................................................................12 
2.2.3. 
Data Review Committee (DRC) ........................................................13 
2.2.4. 
Study Procedures ...............................................................................13 
2.2.5. 
Safety, Efficacy, and Pharmacokinetic Parameters ...........................17 
3.
Patient Population .......................................................................................................19
3.1. 
Population Definitions ....................................................................................19 
3.2. 
Protocol Deviations .........................................................................................19 
4.
General Statistical Methods .......................................................................................20
4.1. 
Sample Size Justification ................................................................................20 
4.2. 
General Methods .............................................................................................20 
4.3. 
Computing Environment ................................................................................20 
4.4. 
Baseline Definitions .........................................................................................20 
4.5. 
Methods of Pooling Data ................................................................................21 
4.6. 
Adjustments for Covariates ...........................................................................21 
4.7. 
Multiple Comparisons ....................................................................................21 
4.8. 
Subpopulations ................................................................................................21 
4.9. 
Withdrawals, Dropouts, Loss to Follow-up ..................................................21 
4.10. Missing Data ....................................................................................................21 
4.11. Visit Windows ..................................................................................................21 
4.12. Interim Analyses .............................................................................................22 
5.
Study Analyses .............................................................................................................23
5.1. 
Patient Disposition ..........................................................................................23 
5.2. 
Demographics and Baseline Characteristics ................................................23 
5.3. 
Safety Analyses ................................................................................................24 
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Section 
Page 
5.3.1. 
Study Drug Exposure .........................................................................24 
5.3.2. 
Adverse Events ..................................................................................25 
5.3.3. 
Laboratory Data .................................................................................26 
5.3.4. 
Vital Signs ..........................................................................................28 
5.3.5. 
Physical Examination .........................................................................28 
5.3.6. 
Electrocardiogram ..............................................................................28 
5.3.7. 
Concomitant Medications ..................................................................29 
5.4. 
Efficacy Analyses .............................................................................................29 
5.4.1. 
Primary Efficacy Analysis .................................................................29 
5.4.2. 
Secondary Efficacy Analyses.............................................................30 
5.4.3. 
Exploratory Analyses .........................................................................30 
5.5. 
Pharmacokinetic Analyses..............................................................................31 
6. 
Changes to Planned Analyses .....................................................................................32 
7. 
References ....................................................................................................................33 
8. 
Clinical Study Report Appendices .............................................................................34 
8.1. 
List of Statistical Tables, Figures, and Listings to be Generated ...............34 
8.2. 
Statistical Table and Figure Shells ................................................................39 
8.3. 
Data Listing Shells ..........................................................................................77 
9. 
Revision History ........................................................................................................121 
9.1. 
Statistical Analysis Plan Version 2.0:  21 April 2017 .................................121 
10. 
Appendices .................................................................................................................123 
10.1. Appendix 1: Classification of Disease Response for Waldenström’s 
Macroglobulinemia .......................................................................................123 
10.2. Appendix 2: IMO-8400 Subcutaneous Injection Site Grading (Local 
Reactions) .......................................................................................................124 
10.3. Appendix 3: Intensity of AE of Injection Site Reaction.............................124 
 
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TABLES INCLUDED IN THE TEXT 
Table 
Page 
Table 2.1 
Planned Dose Escalation Cohorts ........................................................................ 11 
Table 2.2 
Schedule of Study Events .................................................................................... 14 
Table 10.1  
Categorical Response Definitions ...................................................................... 123 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
ATC 
Anatomic Therapeutic Class 
BMI 
Body Mass Index 
CR 
Complete Response 
CSR 
Clinical Study Report 
DLT 
Dose Limiting Toxicity 
DME 
Dose Modifying Event 
DRC 
Data Review Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EE 
Efficacy Evaluable 
EOS 
End-of-Study 
EOT 
End-of-Treatment 
ICH 
International Conference on Harmonization  
IgM 
Immunoglobulin M  
IRB 
Institutional Review Board 
ISR 
Injection Site Reaction 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Minor Response 
MTD 
Maximum Tolerated Dose 
MyD88 
Myeloid differentiation primary response gene (88) 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
ORR 
Objective Response Rate 
PD 
Progressive Disease 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred Term 
Rel Day 
Relative Study Day 
RP2D 
Recommended Phase 2 dose  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Stable Disease (Standard deviation in statistical reference) 
SI 
International System of Units 
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Abbreviation 
Definition 
TEAE 
Treatment-Emergent Adverse Event 
TLR 
Toll-Like Receptor 
VGPR 
Very Good Partial Response 
WHO 
World Health Organization 
WM 
Waldenström’s Macroglobulinemia 
 
 
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1.
STATISTICAL ANALYSIS PLAN OBJECTIVES
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objectives. Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided. The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 
the clinical study report (CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
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2. 
INFORMATION FROM THE STUDY PROTOCOL 
2.1. 
Introduction and Objectives 
2.1.1. 
Introduction 
Waldenström’s Macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder 
characterized by a lymphoplasmacytic infiltrate in the bone marrow and high levels of a 
monoclonal immunoglobulin M (IgM) in the serum (Dimopoulos et al, 2008). The disease can 
have a chronic, indolent course, with patients remaining asymptomatic for years. The principal 
complications include manifestations of the monoclonal gammopathy, including symptomatic 
hyperviscosity, cryoglobulinemia, and cold agglutinin disease; disease-related cytopenia; bulky 
adenopathy or organomegaly; severe neuropathy; amyloidosis; and disease transformation. 
Many of the agents used in refractory or relapsing WM are cytotoxic or sharply 
immunosuppressive and have substantial safety risks in elderly patients that are characteristic of 
this disease. A novel targeted agent that provided a beneficial treatment effect with a better 
tolerability profile would address an unmet need in WM. 
IMO-8400 is a second-generation oligonucleotide antagonist of Toll-like receptors (TLR) 7, 8 
and 9, which blocks immune activation mediated through those receptors. In a Phase 1 study 
IMO-8400 was administered to healthy adults by subcutaneous (SC) injection at single-doses 
and multiple-doses (once weekly for 4 weeks) up to 0.6 mg/kg (see protocol Section 4.4.1 for 
details). All treatments were well-tolerated, with mild injection site reactions and no pattern of 
systemic reactions or laboratory changes. 
In recent studies, a high frequency of mutation in the signaling pathway downstream of TLR7, 8 
and 9 has been identified in patients with B-cell malignancies, including more than 90% of 
patients with WM (Treon et al, 2012). In vitro studies of B-cell tumor lines indicate that such 
mutations are associated with an increase in cell activation, proliferation and survival 
(Young and Staudt, 2013), and that loss of endosomal TLRs results in markedly decreased cell 
proliferation and survival (Lim, Barton, and Staudt, 2013). Data from Idera indicates that 
treatment of such cell lines with IMO-8400 has a similar effect. Further information about the 
preclinical and clinical characteristics of IMO-8400 may be found in the Investigator’s 
Brochure. 
The current study represents the first clinical trial of IMO-8400 in patients with B-cell 
malignancy. 
2.1.2. 
Study Objectives 
2.1.2.1. 
Primary Objective 
The primary objective is to evaluate the safety and tolerability of escalating dose levels of IMO-
8400 administered by SC injection in patients with relapsed or refractory WM. 
2.1.2.2. 
Secondary Objectives 
The secondary objectives are: 
• To assess the treatment effect (clinical activity) of escalating dose levels of IMO-8400 
using disease-specific international guidelines for classifying clinical response 
(Owen et al, 2012). 
• To identify an optimal dose of IMO-8400 for further clinical evaluation. 
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• To characterize the pharmacokinetics of escalating dose levels of IMO-8400 
administered by SC injection. 
2.1.2.3. 
Exploratory Objectives 
The exploratory objectives are:  
• To investigate associations between the treatment effect of IMO-8400 and selected 
biomarkers (e.g., serum cytokines). 
• To correlate the presence of myeloid differentiation primary response gene (88) L265P 
mutation with clinical outcome. 
• To assess the potential immunogenicity of IMO-8400 administered by SC injection. 
2.2. 
Study Design 
2.2.1. 
Synopsis of Study Design  
This is an open-label, multiple-dose, dose escalation study of IMO-8400 in patients with 
relapsed or refractory WM. The overall study design includes Part A, a dose escalation phase to 
investigate the safety and tolerability of planned dose levels of IMO-8400, and Part B, an 
expansion phase to further investigate the efficacy of the maximum tolerated dose (MTD)/ 
recommended Phase 2 dose (RP2D) identified in the escalation phase.  
2.2.1.1. 
Part A: Dose-escalation 
2.2.1.1.1. Dose-escalation Cohorts 
The dose-escalation cohorts (3 to 6 patients each) will systematically evaluate the safety and 
tolerability of IMO-8400 at increasing dose levels in order to identify the MTD/RP2D. See 
Protocol Section 8 for further details on study treatment administration.  
• The planned dose levels are IMO-8400 at 0.6, 1.2, 2.4, and 3.6 mg/kg administered once 
weekly and 1.2 mg/kg administered twice weekly (Table 2.1). Additional dose levels, 
schedules, and routes of administration will be evaluated based on the emerging data. 
Weekly exposure is based on body weight (measured at screening and the start of each 
cycle). Doses will be administered by SC injection. 
• For Dose Level 3 (refer to Table 2.1), the total dose will be divided into 2 equal portions 
(1.2 mg/kg twice weekly), administered as separate SC injections over the course of the 
week, preferably 72 to 96 hours apart (minimum 48 hours).  
• Once safety has been established for the 2.4 mg/kg/week as a divided weekly dose (1.2 
mg/kg twice weekly), the same dose level of 2.4 mg/kg/week and subsequent dose levels 
will be given as a once weekly administration. 
• Once the RP2D/MTD has been established, patients being treated at lower dose levels may 
have their doses escalated to the RP2D/MTD upon discussion and agreement between the 
Sponsor and the Investigator. 
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Table 2.1 Planned Dose Escalation Cohorts 
Dose Level 
IMO-8400 Dose 
(mg/kg) 
Frequency 
Initial Cohort Size 
1 (starting dose) 
0.6 
Once Weekly 
3-6 
2 
1.2 
Once Weekly 
3-6 
3 
1.2 
Twice Weekly 
3-6 
4 
2.4 
Once Weekly 
3-6 
5 
3.6 
Once Weekly 
3-6 
2.2.1.1.2. Dose-escalation Procedures 
Procedures for patient safety during dose-escalation are summarized below and presented in 
detail in the protocol sections and sections of this document indicated: 
• Explicit definitions for identifying suspected adverse reactions as dose-limiting toxicity 
(DLT) events (see Section 2.2.5.1.1). 
• Explicit definition for MTD (see Section 2.2.5.1.1). 
• All injections of study medication will be administered by study personnel and all patients 
observed for 2 hours following the first injection (including the first injection of a new dose 
level in the case of intra-patient dose escalation) and for at least 30 min following all other 
injections. 
• Detailed provisions for management of study drug in individual patients based on safety, 
tolerability, and disease response (see Section 2.2.2.1 and Protocol Section 6.5). 
• Constitution of a Data Review Committee (DRC), comprised of the Idera Medical Monitor 
and Investigators from participating sites, to decide to continue or halt dose-escalation, or 
explore intermediate dose levels (see Section 2.2.3 and Section 2.2.5.1.1). 
2.2.1.1.3. Dose-escalation Enrollment and Review 
Each dose-escalation cohort is expected to enroll at least 3 patients, with a maximum of 6. 
• If the initial 3 patients all complete 4 weeks of treatment without a DLT event, the DRC will 
conduct a dose-escalation review. 
• If 1 of the initial 3 patients experiences a DLT event prior to completing 4 weeks of 
treatment, then enrollment at that dose level will continue to a total of 6 patients and the 
dose-escalation review will be done when all 6 patients have completed 4 weeks treatment. 
• If 2 patients at a dose-level experience DLT events during the first 4 weeks of treatment, 
then no further patients will be enrolled until the DRC completes a review, which should be 
done as soon as feasible. 
The DRC review will include all safety data available for the cohort. The following represent 
anticipated outcomes for the review process. 
• Dose escalation – progression to the next planned dose level. 
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• Continue cohort enrollment (applicable only to review after 3 patients) – enroll up to 6 
patients at the current dose level to obtain additional safety data for subsequent review. 
• Dose de-escalation – enrollment of intermediate levels for exploration of other schedules of 
administration (see Section 2.2.5.1.1). 
• Approve enrollment in the expansion cohort at that dose level, if applicable (see 
Section 2.2.1.2) 
• No further dose escalation enrollment – at this time the DRC will indicate the dose level 
they consider represents the MTD. 
2.2.1.2. 
Part B: Dose Expansion 
2.2.1.2.1. Expansion Cohorts 
The expansion cohorts provide for additional enrollment at agreed upon dose levels to assess the 
dose dependence of clinical response.  
Once the MTD or potential RP2D and schedule have been established during dose escalation, up 
to 22 patients will be treated at the RP2D level according to this schedule. The Sponsor may 
decide at any point during the expansion phase to modify the RP2D based on emerging data 
including, but not limited to, safety, DLTs, pharmacokinetics (PK), and clinical activity. If such 
a change is made, enrollment may continue at the selected dose level in up to 22 patients.  
2.2.2. 
Stopping Rules  
The sponsor reserves the right to discontinue the study for safety or administrative reasons at 
any time. Should the study be terminated and/or the site closed for whatever reason, all 
documentation and study medication pertaining to the study must be returned to the sponsor or 
its representative. 
If the trial is terminated prematurely or suspended, the Sponsor will promptly inform the 
participating Investigators and institutions, the regulatory authorities, and the Institutional 
Review Board (IRB) of the termination or suspension and the reason(s) for the action. 
The maximum exposures to IMO-8400, the investigational agent in this study, will be as 
follows: 
• Maximum number of patients: Approximately 60 patients in planned escalation and 
expansion cohorts; potential for additional patients in contingency cohorts or as 
replacements 
• Maximum dose level: Undefined (pending dose escalation results) - The planned dose 
escalation cohort levels for IMO-8400 are 0.6, 1.2, 2.4, and 3.6 mg/kg administered once 
weekly and 1.2 mg/kg administered twice weekly 
• Maximum treatment duration: Undefined (treatment is until study completion or until the 
patient experiences intolerable toxicity, disease progression, or withdraws consent, 
whichever comes first) 
2.2.2.1. 
Stopping Rules for Individual Patients 
In Protocol Versions <6, the duration of treatment is up to 24 weeks, with the option to extend 
treatment in the extension protocol, Study 8400-404. In Protocol Versions ≥6, treatment will 
continue until the patient experiences intolerable toxicity, disease progression, or withdraws 
consent, whichever occurs first.  
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Each enrolled patient will receive IMO-8400 at the assigned dose level until the earliest of: 
• Clinical DLT event – see Section 2.2.5.1.1  
• Disease progression – based on assessments at Week 1 of each cycle. Unscheduled 
assessments may be conducted in response to new clinical observations. Disease status will 
be classified according to international guidelines (Owen et al, 2012) (see Section 10.1 for 
details) 
• Termination of participation in the study – due to adverse event (AE), withdrawal of 
consent, intolerable toxicity, or loss to follow up.  
Study treatment will be discontinued for DLT clinical events and for disease progression (based 
on discussion between the Sponsor and Investigator – See Protocol Section 6.5.1). For DLT 
laboratory events and dose modifying events (DMEs; clinically significant toxicities or DLTs 
that occur after 5 weeks of treatment), provision is made for pausing treatment for up to 3 weeks 
and, if the acute toxicity improves sufficiently, resuming treatment at a lower dose level (see 
Protocol Section 6.5.2 for details). The Investigator will review with the Medical Monitor 
decisions to discontinue, pause, and/or start study treatment. 
2.2.3. 
Data Review Committee (DRC) 
The Data Review Committee will be comprised of the Idera Medical Monitor and Investigators 
from participating sites to decide whether to continue or halt dose escalation, or explore 
intermediate dose levels.  
A patient will be considered evaluable for purposes of DRC review if they meet either of the 
following criteria: 
• Received at least 1 dose of study drug and had treatment discontinued because of a DLT 
event as defined in Protocol Section 6.3.1 or 
• Received all doses of study drug in the first 4 weeks of treatment and completed Week 5 
assessment procedures. 
2.2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 2.2,The 
schedule is presented relative to the day and time of dosing. All Days are relative to the day of 
the first injection of study drug, designated Day 1. All weeks are relative to Week 1, defined as 
Day 1 through Day 7, inclusive. All times are relative to injection, designated 0 hr; “pre-dose” 
vital signs are to occur within 1 hour prior to injection; all other pre-dose procedures are to 
occur prior to injection on the same calendar day. 
The screening evaluation may be performed up to 21 days prior to dosing.  
Laboratory assessments for disease status will be conducted at Screening, every 4 weeks ± 1 
week (Week 1 and Week 5 of each cycle), every 12 weeks ± 4 weeks during the Follow-up 
Phase, at the end-of-treatment (EOT) visit, and at the end-of-study (EOS) visit. Radiologic 
imaging and bone marrow biopsy will be performed at Screening and at EOT visit or as 
clinically indicated. 
The criteria for response to treatment will be classified using disease-specific criteria as 
proposed by the VIth International Workshop on Waldenström’s Macroglobulinemia 
(Owen et al, 2012) (see Section 10.1). 
 
 
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Table 2.2 
Schedule of Study Events 
Visit1 
Scrn2 
Day 1 
Treatment Period 
EOT3 
 
EOS3 
 
Follow-up 
Cycle 
Cycle 1 
Even Numbered 
Cycles 
Odd Numbered Cycles 
Every 12 weeks 
(± 4 weeks)  
Week 
Evaluation 
 
 
2-4 
5 
6-8 
1 
2-
4 
5 
6-8 
1 
2-4 
5 
6-8 
 
 
 
Informed Consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients who 
discontinue for 
reasons other 
than progressive 
disease should 
be assessed per 
Response 
Assessment in 
WM24 until 
documentation 
of progressive 
disease, start of 
new anti-cancer 
therapy, until 
the study ends, 
or for up to 6 
months from the 
last patient’s 
first treatment 
cycle, whichever 
one comes first.  
 
Inclusion/ Exclusion  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cryoglobulin & Cold Agglutinin Lab 
Tests6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination8 
X 
X 
X8 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Body weight7 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Height measurement  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs9,10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment for Tumor 
Status11 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Total IgM & Monoclonal Protein Lab 
Tests12  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
ECOG7 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
CT or MRI imaging13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Safety Laboratory Tests14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis7 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
12-lead ECG15 
X 
X15 
 
X15 
 
X15 
 
X15 
 
X15 
 
X15 
 
X 
 
Pregnancy test (females only)16 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK17  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Serum Cytokines18 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Antibodies to IMO-840018 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Serum NF-κB19 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Initial Dx Bone Marrow Slides20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Biopsy& Aspirate21  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Assessment of Injection Site22  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Administration10,23 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AE & Concomitant Med Monitoring 
From Screening to EOS Visit 
 
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Abbreviations: AE=adverse event; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOS=end-of-study; 
EOT=end-of-treatment; IgM=immunoglobulin M; NF-қB=nuclear factor kappa-light-chain-enhancer of activated B cells; PK=pharmacokinetic; MRI=magnetic 
resonance imaging; Scrn=Screening; WM=Waldenström’s macroglobulinemia  
1 Day 1 is the day of the first injection of study drug. All weeks for a given cycle are relative to the day of the first injection of study drug for that Cycle and are 
defined as Day 1 through Day 7, inclusive; all times are relative to injection, designated 0 hour; “pre-dose” vital signs are to occur within 1 hour prior to 
injection; all other pre-dose procedures are to occur prior to injection on the same calendar day.  
2 Screening procedures may be performed up to 21 days prior to Day 1.  
3 If treatment is terminated prematurely for any reason, the EOT visit will be performed within 5 days of the decision to terminate; the EOS visit will be 
performed 30 to 35 days after the last dose of study drug.  
4 Informed consent must be signed prior to all study-specific screening procedures.  
5 Medical history includes, but is not limited to, a detailed review of the patient’s malignancy, prior treatments, relevant current or past abnormalities or diseases, 
and signs and symptoms of WM at baseline.  
6 Cryoglobulin and cold agglutinin laboratory testing to be performed at Screening (local laboratory). 
7 To occur pre-dose  
8 During Cycle 1 only, physical examination will be done on Week 2. In subsequent cycles, physical examinations will be done every 4 weeks.  
9 Vital signs comprise heart rate, blood pressure, respiratory rate and temperature. Vital signs will be obtained pre-dose (within 1 hour prior to injection) and 
post-dose at 30 (± 5) min after dosing. On Day 1 of Cycle 1, Week 1, post-dose vital signs will also be obtained at 2 hours (± 20 min).  
10 For patients who receive a second weekly dose, vital signs will be obtained pre-dose (within 1 hour prior to injection) and post-dose at 30 (± 5) min after 
dosing, and assessment of the injection site, as previously noted, will be conducted.  
11 Clinical assessment for tumor status will be conducted pre-dose on dosing visits and will include assessment for lymphadenopathy, hepatomegaly, and 
splenomegaly (see Protocol Section 9.4.1 for details).  
12 Assessments will be conducted pre-dose on dosing visits, and includes total serum IgM, monoclonal serum IgM, serum free light chains, urine free light 
chains, serum viscosity, and serum β2-microglobulin; see Protocol Section 9.4.2 for details.  
13 CT or MRI imaging of chest, abdomen, and pelvis with the same modality used for every assessment; see Protocol Section 9.4 for details. 
14 The full panel of safety laboratory tests (hematology, serum complement, chemistry and coagulation) will be done pre-dose on Day 1, and Weeks 1 and 5 of 
each cycle (including pre-treatment criteria presented in Protocol Section 8.4.1); a focused panel (hematology, selected chemistry) will be done pre-dose on 
Weeks 3 and 7 of each cycle; see Protocol Section 9.7.1 for details. Unscheduled tests to confirm decreases in serum complement levels will be performed (see 
Protocol Section 6.5.4). 
15 ECGs are to be performed pre-dose and 2 hours post-dose on Day 1 of Cycle 1 and pre-dose at the first dosing visit of Weeks 1 and 5 of each cycle thereafter. 
In addition, an ECG is to be performed at 2 hours post-dose on Day 1 of each odd-numbered cycle. 
16 Serum pregnancy testing will be done pre-dose and evaluated at the central laboratory. 
17 PK samples will be collected as scheduled in relation to the first dose administered on Day 1 of every cycle. Samples will be obtained pre-dose (within 1 hour 
prior to injection) and post-dose at 1 hour (± 5 min), 2 hours (± 10 min) and 4 hours (± 15 min) after dosing. PK samples will also be taken at EOT and EOS. 
18 Serum for cytokines and antibodies to IMO-8400 will be collected as scheduled in relation to the first dose administered on Day 1 of every cycle and will be 
obtained pre-dose (within 1 hour prior to injection). 
19 Serum samples for NF-қB analysis will be obtained pre-dose (within 1 hour prior to injection) and post-dose at 4 hours (± 15 min) (see Protocol Section 9.9 for 
details) and will be submitted to central laboratory. 
20 Bone marrow slides will be obtained from initial WM diagnosis. 
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21 Bone marrow biopsy and aspirate will be collected at Screening, EOT, and to document complete response as appropriate (see Protocol Section 16.2) and 
submitted to central laboratory (see Protocol Sections 9.4.4 and 12.4.1). If patients have a bone marrow biopsy within 4 weeks of EOT, the biopsy will not be 
repeated at EOT. The Screening Visit sample will also be assayed for the MyD88 L265P mutation. 
22 Assessment of all prior injection site(s) with grading and measurement of any reaction (see Protocol Section 9.6.5). In addition, on dosing days, the planned 
injection site will be assessed to confirm it is appropriate for use. 
23 Schedule applies to all patients receiving once weekly dosing and to the first weekly dose for all patients receiving twice weekly dosing (see Protocol Sections 
1.3.2 and 8.4 for details). 
24 Response assessment is summarized in Protocol Section 16.2 and includes total serum IgM, serum monoclonal IgM, bone marrow histology, 
adenopathy/organomegaly, cytopenias, and symptoms (see Protocol Section 9.5 for details). Total IgM and monoclonal protein lab tests (see Protocol Section 
9.4.2 for details) will be submitted to central laboratory. 
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2.2.5. 
Safety, Efficacy, and Pharmacokinetic Parameters 
2.2.5.1. 
Safety Parameters 
The safety and tolerability of IMO-8400 will be assessed using reported and observed adverse 
events (AEs) as well as scheduled safety observations including vital signs, symptom review, 
physical examination, laboratory tests (hematology, serum complement, clinical chemistry, and 
coagulation), urinalysis, electrocardiograms (ECGs), and reported and observed ISRs. 
Additional unscheduled assessments will be performed at the Investigator’s discretion.  
Adverse events will be graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) Version 4.03. Adverse Events will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA) version 16.0 and tabulated by event, 
grade, and relationship to study therapy. Laboratory results, vital signs, and ECG parameters 
will be summarized using descriptive statistics. Laboratory values will also be graded according 
to NCI CTCAE, Version 4.03, and summarized using shift tables. Injection site reactions will be 
summarized by incidence and time-to-event analyses will be performed. Details for the injection 
site grading and the intensity scale for reporting ISR AEs are located in Section 10.2 and 
Section 10.3. 
2.2.5.1.1. Definition of Dose Limiting Toxicity and Maximum Tolerated Dose 
A DLT can be either a clinical or laboratory AE. A potential DLT event is defined as a 
treatment-emergent AE that meets any of the following criteria using NCI CTCAE v4.03 
grading:  
• Is a clinical event of Grade 3 or higher severity, except for the following: 
• Alopecia  
• Grade 3 fatigue 
• Grade 3 nausea/vomiting that has not been treated with optimal anti-emetic treatments  
• Grade 3 diarrhea that has not been treated with optimal anti-diarrheal treatments  
• AE related to the underlying disease  
• Is a confirmed laboratory finding of Grade 3 or higher severity and has been assessed as 
related to IMO-8400 (any relationship other than “not related”) with the exceptions of 
neutropenia and thrombocytopenia. DLTs with respect to neutropenia/thrombocytopenia are 
outlined below: 
• Grade 4 neutropenia lasting > 7 days  
• Grade 3 or 4 neutropenia with a sustained temperature > 101.3º F  
• Grade 3 thrombocytopenia associated with clinically significant bleeding that requires 
transfusion therapy  
• Grade 4 thrombocytopenia  
Clinically significant toxicities or DLTs that occur after Week 5 of Cycle 1, are defined as 
DMEs and may be considered when determining the RP2D. 
The DRC will review all potential DLT events to assess causality, i.e., relationship to study drug 
(related, possibly related, unlikely related, or not related). Events will be considered DLT events 
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unless they are unanimously assessed as “Not related”, that is, a factor other than study drug is 
the cause of the event.  
The MTD is the dose level meeting both of the following criteria: 
• It is below the level at which 2 or more patients experienced DLTs during the first four 
weeks of treatment; 
• It is a dose level at which no more than 1 patient experienced DLTs during the first four 
weeks of treatment. 
The RP2D will be a dose at or below the MTD based on clinical data. 
2.2.5.2. 
Efficacy Parameters 
Overall disease response reported is investigator-assessed, using disease-specific international 
guidelines for classifying clinical response (Owen et al, 2012). 
The primary treatment effect parameter is objective response rate (ORR), defined as the 
occurrence of complete response (CR), very good partial response (VGPR), partial response 
(PR), or minor response (MR), presented by dose level and overall.  
Secondary efficacy endpoints include: 
• The distribution of response classes identified by best overall response  
• Time to progression – Time from initiation of treatment to the first documented evidence of 
disease progression, with deaths due to unrelated causes censored. 
• Progression-free survival (PFS) – Time from the initiation of treatment to disease 
progression or death from any cause. 
• Time to best observed response – Time from the initiation of treatment to the first 
occurrence of the best observed category of response.  
• Percent and absolute change in quantitative serum levels of monoclonal and total IgM. 
Exploratory endpoints include the following investigational factors, analyzed with regard to 
disease status: 
• Presence or absence of MyD88 L265P and CXCR4 mutation in tumor cells 
• Serum cytokine levels and change from baseline 
• Serum levels of antibody to IMO-8400 
• NF-κB inhibition 
• Absolute change from baseline in hemoglobin and platelet levels 
Additional exploratory analysis may be performed on additional endpoints of interest or 
subpopulations. 
2.2.5.3. 
Pharmacokinetic Parameters 
Details regarding PK parameters and analysis will be described in a separate PK SAP and 
report. 
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3. 
PATIENT POPULATION 
3.1. 
Population Definitions 
The following patient populations will be evaluated and used for presentation and analysis of 
the data: 
Safety Population:  All patients who received at least one dose of study treatment. 
Efficacy Evaluable (EE) Population – all patients who completed ≥1 cycle of therapy (i.e. at 
least 8 weeks of at least one dose of treatment) or those who discontinued due to progressive 
disease or DLT. 
3.2. 
Protocol Deviations 
For protocol deviations relating to individual patients, the event and relevant circumstances will 
be recorded on source documents and on the appropriate electronic case report form (eCRF). 
Protocol deviations will be determined and documented prior to database lock. 
All protocol deviations will be presented in a data listing. 
Relevant Output 
Listing 16.2.2.2 
Protocol Deviations 
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4. 
GENERAL STATISTICAL METHODS 
4.1. 
Sample Size Justification 
Consistent with the primary objective, the study design represents a pragmatic assessment of 
safety and tolerability across different dose levels of IMO-8400 based upon clinical evaluations 
and laboratory tests. 
Following identification of the MTD/RP2D, up to an additional 22 patients will be enrolled at 
the MTD or proposed RP2D level. With a total sample size of 22 patients, there is a 90% 
probability to detect an AE with a true incidence rate of 10%. A secondary objective of this 
study is to determine the treatment effect of IMO-8400 in patients enrolled at the MTD/RP2D. 
Using the exact binomial distribution with a 1-sided test and an alpha of 0.05, there is 79% 
power to detect a response rate of 33% as compared to a null response rate of 10%. 
4.2. 
General Methods 
All data listings that contain an evaluation date will contain a relative study day (Rel Day). 
Relative study days are defined as follows:  
• Rel Day 1 is defined as the calendar day of the first injection of study drug. 
• The days prior to Rel Day 1 are designated Rel Day –1, Rel Day –2, etc; there is no Rel 
Day 0. 
• The days following the day of the first injection of study drug are designated Rel Day 2, Rel 
Day 3, etc. 
• The times of events related to dosing of study drug will be designated as minutes or hours 
before or after the time of dosing (i.e., the subcutaneous injection of study drug), which is 
designated as t = 0 (zero). Thus, 15 minutes prior to dosing is t = –15 min; 2 hour after 
dosing is designated t = 2 h. 
All output will be incorporated into Microsoft Word files, sorted and labeled according to the 
International Conference on Harmonisation (ICH) recommendations, and formatted to the 
appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety 
parameters. For categorical variables, summary tabulations of the number and percentage of 
patients within each category (with a category for missing data) of the parameter will be 
presented. For continuous variables, the number of patients, mean, median, standard deviation, 
minimum, and maximum values will be presented. For some efficacy parameters, a confidence 
interval will also be presented, as described in Section 5.  
Data will be listed by patient and dose and summarized by dose and overall. All data will be 
included in summary tabulations. 
4.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.3 
or above, unless otherwise noted. 
4.4. 
Baseline Definitions 
For all measures, baseline will be defined as the most recent measurement prior to the first 
administration of study drug. 
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4.5. 
Methods of Pooling Data 
Data will be pooled across all study sites. All IMO-8400 dosed patients will be pooled together 
and presented separately by dose level. 
4.6. 
Adjustments for Covariates 
Exploratory efficacy analyses for efficacy endpoints may be done by the presence or absence of 
relevant mutations (e.g. MyD88 L265P or CXCR4); the presence or absence of these mutations 
may be included in a model as a covariate if any modeling analyses are done. 
4.7. 
Multiple Comparisons 
No adjustments for multiple comparisons will be made. As the primary purpose of this study is 
to assess the safety and tolerability of IMO-8400, efficacy assessments are secondary and the 
type I error rate will not be adjusted. 
4.8. 
Subpopulations 
Efficacy analyses may be done on the subpopulation of ibrutinib-refractory patients. Select 
efficacy laboratory parameters will be summarized for the subpopulation of patients who have 
not received a transfusion during the course of the study.  
4.9. 
Withdrawals, Dropouts, Loss to Follow-up 
A patient who does not meet the criteria for “evaluable” as explained above in Section 2.2.3 
may be replaced to assure the requirements for completing the cohort are met. Replacement 
patients will be identified by distinctive patient numbers and will receive the same dose level as 
the patient being replaced. 
4.10. 
Missing Data 
Missing data will not be imputed, except as described in this section. All the data recorded on 
the eCRF will be included in data listings that will accompany the CSR. 
When tabulating AE data, partial dates will be imputed as follows. If the day of the month is 
missing, the onset day will be set to the first day of the month unless it is the same month and 
year as study treatment. In this case, to conservatively report the event as treatment-emergent, 
the onset date will be assumed to be the first date of treatment. If the onset day and month are 
both missing, the day and month will be assumed to be January 1, unless the event occurred in 
the same year as the study treatment. In this case, the event onset will be coded to the day of 
treatment in order to conservatively report the event as treatment-emergent. A missing onset 
date will be coded as the first day of treatment. Listings will present all data as reported (i.e., 
without imputations). 
When tabulating time since initial diagnosis and time since most recent therapy for disease 
history, partial dates will be handled as follows. If the day of the month is missing, the day will 
be set to the last day of the month. If both the date and month are missing, the day and month 
will assumed to be December 31. 
4.11. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule; visits outside of this 
schedule will be listed as a protocol deviation. Visits occurring outside of the visit windows as 
described in the protocol schedule will be included in summary tabulations if corresponding to a 
scheduled visit. Unscheduled assessments will not be summarized in tabulations that present 
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data by visit. However, in shift tables or summaries of best response, data from unscheduled 
assessments will be included. All data will be provided in listings, including the relative day of 
all dates presented. 
4.12. 
Interim Analyses 
Interim safety data will be examined on an ongoing basis to ensure patient safety and to comply 
with the clinical trial dose escalation rules. There is no formal interim analysis planned for 
efficacy.  
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5. 
STUDY ANALYSES 
5.1. 
Patient Disposition 
Patient disposition will be tabulated and will include the number enrolled (i.e. treated) at each 
dose level, the number prematurely discontinued from treatment, the reason for discontinuation, 
and the number in each analysis population.  
A by-patient data listing of study completion information including the reason for premature 
study withdrawal and premature treatment discontinuation will be presented. A by-patient data 
listing of inclusion/exclusion criteria not met will also be presented. 
Relevant Output 
Table 14.0.1  
Treatment Codes Applicable to Tables and Listings 
Table 14.1.1.1  
Patient Enrollment and Disposition 
Listing 16.2.1.1 
Patient Disposition 
Listing 16.2.1.2 
End of Treatment (EOT) Visit Status  
Listing 16.2.1.3 
End of Study (EOS) Visit Status  
Listing 16.2.2.1 
Inclusion/Exclusion Criteria Not Met 
Listing 16.2.3.1 
Study Populations 
5.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics, including medical and disease history, will be 
summarized and presented by dose level and overall. Ethnicity, race, sex, age, height, weight, 
body mass index (BMI), baseline ECOG Performance Status, and presence or absence of 
MyD88 L265P or CXCR4 mutation in tumor cells will be summarized. 
Disease history will include years since initial diagnosis, baseline International Prognostic 
Scoring System for WM (IPSSWM) category (low, med, high), and baseline values of the 
following laboratory parameters: total IgM, monoclonal IgM, hemoglobin, platelet count, and 
β2 microglobulin. Baseline signs and symptoms of WM will also be summarized. 
The IPSSWM category is derived as follows:  
1) Except for age, each of the below factors (at baseline) is worth a single point. The points are 
added to make a score, which is used to divide patients into 3 risk groups: 
a) Age more than 65 years old 
b) Blood hemoglobin level 11.5 g/dL or less 
c) Platelet count 100,000/mcL or less 
d) Beta-2 microglobulin more than 3 mg/L 
e) Monoclonal IgM level more than 7 g/dL 
2) Using the points identified in step 1, the risk groups as assigned as follows:  
a) Low-risk = patients 65 or younger who have no more than 1 point 
b) Intermediate-risk = patients who are older than 65 with 2 or fewer points, and those 65 
or younger who have 2 points 
c) High-risk = patients of any age who have at least 3 points 
A summary of prior treatments will include number and percentage of patients who have 
received at least one prior therapy, including type of treatment, best overall response, and reason 
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for discontinuation of therapy. Number of prior therapies will be summarized both continuously 
and categorically (i.e., 1, 2, 3, or 4+ prior therapies). Number of days since most recent therapy 
will also be summarized.  
Demographic, baseline, and medical history data for each patient will be provided in data 
listings.  
Relevant Output 
Table 14.1.2.1 
 
Demographic Characteristics (Safety Population) 
Table 14.1.2.2 
 
Baseline Characteristics (Safety Population) 
Table 14.1.3.1 
 
Disease History and Baseline Disease Characteristics (Safety Population) 
Table 14.1.4.1 
 
Prior Treatments (Safety Population) 
Table 14.1.5.1 
Baseline Waldenström’s Macroglobulinemia Symptoms (Safety 
Population) 
Listing 16.2.4.1 
 
Demographic Characteristics  
Listing 16.2.4.2 
 
Medical History 
Listing 16.2.4.3 
 
Waldenström’s Macroglobulinemia Disease History  
Listing 16.2.4.4 
 
Prior Waldenström’s Macroglobulinemia Therapy 
Listing 16.2.4.5 
 
Baseline Waldenström’s Macroglobulinemia Symptoms 
Listing 16.2.4.6 
 
MyD88 L265P or CXCR4 Mutation Status 
Listing 16.2.9.3 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
5.3. 
Safety Analyses 
Safety observations will be analyzed using descriptive statistics and tabulation. No formal 
statistical comparisons are planned. All safety data will be presented in listings. 
5.3.1. 
Study Drug Exposure 
Study drug exposure will be tabulated by the number of cycles of study drug received, where a 
completed cycle is defined at receiving 8 weeks of at least one dose of treatment for that cycle. 
The number and percentage of patients will be reported by dose group and overall.  
Cumulative exposure to IMO-8400 (mg) will be summarized by dose group and overall, where 
cumulative exposure is the actual dose received summed across all visits. The actual dose for 
each injection will be calculated as follows:  
Dose (mg) = [assigned dose (mg/kg) * volume administered (mL)] / concentration of 0.007 
(mL/kg) 
The total number of doses received will be summarized. The number of missed doses will also 
be tabulated, as well as the reason the dose was missed per patient (i.e. if a patient missed 
multiple doses for the same reason, they will only be counted once for that reason).  
Dosing information for each patient will be presented in a data listing.  
Relevant Output 
Table 14.3.5.1 
Study Drug Exposure (Safety Population) 
Listing 16.2.5.1 
Study Drug Exposure 
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5.3.2. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system and displayed in tables and 
data listings using system organ class (SOC) and preferred term. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as:  
− any AE with onset after the first administration of study medication (Day 1) through the 
EOS visit,  
− any AE that was present at baseline but worsened in intensity or was subsequently 
considered drug-related by the Investigator through the EOS visit, or 
− any AE with missing onset date.  
The incidence of treatment-emergent AEs (TEAEs) will be presented by individual and pooled 
dose levels. For each tabulation, TEAEs are summarized by patient incidence rates; therefore, in 
any tabulation, a patient contributes only once to the count for a given TEAE (SOC or preferred 
term), irrespective of the number of episodes of a particular TEAE term reported. No formal 
hypothesis-testing analysis of AE or TEAE incidence rates will be performed. 
An overview summary of the number and percentage of patients with any TEAE, TEAE related 
to study drug, grade ≥3 TEAE, serious TEAE (SAE), DLT, TEAE leading to death, and TEAE 
leading to premature discontinuation of study treatment will be presented.   
Additional summary tables by SOC and preferred term will be produced for the following:  
• All TEAEs 
• All TEAEs by relationship to study drug (drug-related, not drug-related) where drug-related 
AEs include events with probable, possible and missing relationships 
• All non-serious TEAEs 
• All serious TEAEs 
• All TEAEs by highest severity grade (grade 1 or 2, grade 3, or grade ≥4) 
• All DLTs 
For each injection site, local ISRs will be summarized by the worst grade post-treatment for 
each symptom. Pain, tenderness, pruritus, and induration will be summarized using number and 
percentage of patients by toxicity grade and overall. Blisters, ulceration, erythema, and necrosis 
measurements (mm) will be summarized descriptively, including quartiles and 90th percentiles, 
as well as categorically by grade. For each injection site the worst grade post treatment is 
counted per patient and symptom. In addition, each symptom will be summarized over time by 
visit and grade and overall.  
All AEs occurring from the date of signed informed consent through the end of the study will be 
listed. Additionally, a glossary of AE verbatim terms by preferred term and SOC will be 
provided. A separate listing for system organ class complete name and their corresponding 
abbreviations will be provided.  
By-patient listings will also be provided for the following:  patient deaths, SAEs, DLTs, and 
TEAEs leading to premature discontinuation of study treatment. 
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Relevant Output 
Table 14.3.1.1 
Summary of Treatment-Emergent Adverse Events (Safety Population) 
Table 14.3.1.2 
Incidence of Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.3 
Incidence of Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term and Strongest Relationship to Study 
Drug (Safety Population) 
Table 14.3.1.4 
Incidence of Non-Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.5 
Incidence of Serious Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.6 
Incidence of Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term and by Highest Grade (Safety 
Population) 
Table 14.3.1.7 
Incidence of Dose-Limiting Toxicity Adverse Events by MedDRA 
System Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.8 
Incidence of Observed Local Injection Site Reactions by Worst Grade 
Post Baseline (Safety Population) 
Table 14.3.1.9 
Incidence of Observed Local Injection Site Reactions by Worst Grade 
and Scheduled Visit (Safety Population) 
Table 14.3.2.1 
Listing of Adverse Events Leading to Death 
Table 14.3.2.2 
Listing of Serious Adverse Events  
Table 14.3.2.3 
Listing of Dose Limiting Toxicities  
Table 14.3.2.4 
Listing of Premature Treatment Discontinuations Due to Adverse Events 
Listing 16.0.1 
System Organ Class Abbreviations 
Listing 16.2.7.1 
Adverse Events by Patient and System Organ Class / Preferred Term  
Listing 16.2.7.2 
Adverse Events by System Organ Class / Preferred Term  
Listing 16.2.7.3 
Glossary of Adverse Event Verbatim Terms by MedDRA System Organ 
Class, Preferred Term, and Patient 
Listing 16.2.7.4 
Injection Site Reaction Assessments 
Listing 16.2.7.5 
Patient Reported Injection Site Reactions 
Listing 16.2.7.6 
Observed Injection Site Reactions  
5.3.3. 
Laboratory Data 
Clinical laboratory values will be reported in US units. 
This study collects central laboratory data, but in some instances local laboratory data may be 
collected. Local laboratory data will not be summarized but it will be included in the laboratory 
listings. The final central laboratory data will not be incorporated into the electronic data capture 
(EDC) system; the data, including the normal laboratory ranges, will be in Excel format sent 
directly from the central laboratory. The local laboratory data will be incorporated into the EDC 
system, but local laboratory ranges will be collected externally in Excel format.  
The actual value and change from baseline to each scheduled evaluation will be summarized for 
hematology, chemistry, coagulation, and serum complement parameters.  
Laboratory CTCAE grades shift from baseline to the worst grade post baseline will be tabulated 
for individual and pooled dose groups using number and percentage of patients. These 
comparisons will include values from unscheduled visits.  
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All laboratory data will be provided in data listings, including cryoglobulins, cold agglutinins, 
serology, and pregnancy test data, separately for local and central laboratory results. Out of 
range values will be flagged as H or L, corresponding to high or low.  Local laboratory listings 
will flag values that are considered to be clinically significant by the investigator. 
Relevant Output: 
Table 14.3.5.2A 
Summary and Change from Baseline for Hematology Parameters by 
Scheduled Visit and Dose Group (Safety Population) 
 
Table 14.3.5.2B 
Summary and Change from Baseline for Chemistry Parameters by 
Scheduled Visit and Dose Group (Safety Population)  
 
Table 14.3.5.2C 
Summary and Change from Baseline for Coagulation Parameters by 
Scheduled Visit Point and Dose Group (Safety Population)   
Table 14.3.5.2D 
Summary and Change from Baseline for Serum Complement Parameters 
by Scheduled Visit and Dose Group (Safety Population) 
Table 14.3.5.3A 
Shifts from Baseline to Worst CTCAE Grade Post-Baseline in 
Hematology Parameters by Dose Group (Safety Population)  
Table 14.3.5.3B 
Shifts from Baseline to Worst CTCAE Grade Post-Baseline in Chemistry 
Parameters by Dose Group (Safety Population)  
Table 14.3.5.3C 
Shifts from Baseline to Worst CTCAE Grade Post-Baseline in 
Coagulation Parameters by Dose Group (Safety Population) 
Listing 16.2.8.1A 
Central Laboratory Results: Hematology – Part 1 
 
Listing 16.2.8.1B 
Central Laboratory Results: Hematology – Part 2 
Listing 16.2.8.1C 
Local Laboratory Results: Hematology – Part 1 
Listing 16.2.8.1D 
Local Laboratory Results: Hematology – Part 2 
Listing 16.2.8.2A 
Central Laboratory Results: Chemistry – Part 1 
Listing 16.2.8.2B 
Central Laboratory Results: Chemistry – Part 2  
Listing 16.2.8.2C 
Central Laboratory Results: Chemistry – Part 3 
Listing 16.2.8.2D 
Local Laboratory Results: Chemistry – Part 1 
Listing 16.2.8.2E 
Local Laboratory Results: Chemistry – Part 2 
Listing 16.2.8.2F 
Local Laboratory Results: Chemistry – Part 3 
Listing 16.2.8.3A 
Central Laboratory Results: Urinalysis – Part 1 
Listing 16.2.8.3B 
Central Laboratory Results: Urinalysis – Part 2 
Listing 16.2.8.3C 
Central Laboratory Results: Urinalysis – Part 3 
Listing 16.2.8.3D 
Central Laboratory Results: Urinalysis – Part 4 
Listing 16.2.8.3E 
Central Laboratory Results: Urinalysis – Part 5 
Listing 16.2.8.3F  
Local Laboratory Results: Urinalysis – Part 1 
Listing 16.2.8.3G 
Local Laboratory Results: Urinalysis – Part 2 
Listing 16.2.8.3H 
Local Laboratory Results: Urinalysis – Part 3 
Listing 16.2.8.4A 
Central Laboratory Results: Coagulation 
 
Listing 16.2.8.4B 
Local Laboratory Results: Coagulation 
Listing 16.2.8.5A 
Central Laboratory Results: Serum Complement 
Listing 16.2.8.5B 
Local Laboratory Results: Serum Complement 
Listing 16.2.8.6 
Local Laboratory Results: Cryoglobulins 
Listing 16.2.8.7 
Local Laboratory Results: Cold Agglutinins 
Listing 16.2.8.8 
Laboratory Results: Serology 
Listing 16.2.8.9 
Pregnancy Test Results 
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5.3.4. 
Vital Signs 
The actual value and change from baseline to each on-study evaluation will be summarized for 
vital signs, including heart rate, blood pressure, respiratory rate, and temperature in degrees 
Celsius. 
Vital sign measurements will be presented in a data listing. 
Relevant Output: 
Table 14.3.5.4 
Summary and Change from Baseline for Vital Signs by Scheduled Visit 
and Dose Group (Safety Population) 
Listing 16.2.9.1 
Vital Signs 
5.3.5. 
Physical Examination 
All physical examination findings will be provided in a data listing.   
Relevant Output: 
Listing 16.2.9.2  
Physical Examination Findings 
5.3.6. 
Electrocardiogram 
Actual ECG values and change from baseline will be summarized descriptively by scheduled 
visit, including heart rate and PR, QRS, QT, and QTcF (calculated by the Fridericia correction 
formula). QTcF will be calculated using the formula QT/(RR1/3). If the RR interval is not 
collected, it will be calculated as 60 divided by the heart rate. 
There will be a categorical summary of QTcF intervals, where the number and percent of 
patients experiencing a QTcF interval above the following limits between C1W1 and EOS will 
be summarized: >450, >480, and >500. Note that patients may be counted multiple times if 
applicable, for instance a patient with a maximum QTcF value of 520 would be counted in all 3 
categories. Additionally, the number and percent of patients experiencing changes from baseline 
in the QTcF interval of >30 and >60 will be summarized. 
QTcF intervals will also be summarized using the following categories: ≤450, 451-480, 481-
500, >500 shift from baseline to each scheduled post-baseline value. A shift table will also be 
presented for heart rate using the following categories: <60 bpm, 60-100 bpm, and >100 bpm. 
The table will present shift from baseline to the greatest and smallest post baseline values using 
these categories. 
Shift tables will be tabulated for individual and pooled dose groups using number and 
percentage of patients. ECG summaries by visit will use nominal visit and not include 
unscheduled values. Tables not summarized by visit will include all values, including 
unscheduled visits. 
Electrocardiogram data will be provided in a data listing. 
Relevant Output: 
Table 14.3.5.5 
Summary and Change from Baseline for Electrocardiogram Results by 
Scheduled Visit and Dose Group (Safety Population) 
Table 14.3.5.6 
Categorical Summary of QTcF Interval by Dose Group (Safety 
Population) 
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Table 14.3.5.7 
Shifts in QTcF Interval from Baseline by Scheduled Visit and Dose 
Group (Safety Population) 
Table 14.3.5.8  
Shifts in Heart Rate Category from Baseline to Greatest and Lowest Post-
Baseline Values by Dose Group (Safety Population) 
Listing 16.2.9.4 
12-Lead Electrocardiogram Interval and Overall Assessment 
5.3.7. 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary Version Q12013 (or later). Results will be tabulated by anatomic therapeutic class 
(ATC) and preferred term. 
Any medications that did not end prior to first dose will be classified as a concomitant 
medication, as well as medications that are ongoing or those missing the end date. In case of 
repeated occurrences per patient, a medication will only be counted once per ATC/preferred 
term. 
The use of concomitant medications will be included in a by-patient data listing. 
Relevant Output: 
Table 14.3.5.9 
Concomitant Medications (Safety Population) 
Listing 16.2.9.5 
Concomitant Medications 
5.4. 
Efficacy Analyses 
All efficacy analyses will be done using the Efficacy Evaluable (EE) Population, with select 
parameters repeated using the Safety Population as described in this section. 
For patients who discontinue study treatment for any reason and start another treatment of their 
malignancy, all subsequent response assessments from the date of start of another treatment will 
be excluded from the analysis. 
5.4.1. 
Primary Efficacy Analysis 
The primary statistical analysis of efficacy will be performed on the investigator-assessed 
objective response rate (ORR), defined as the number of patients with a best response of MR, 
PR, VGPR, or CR divided by the number of patients in the EE Population. The ORR will be 
presented by dose level and overall with corresponding 90% confidence intervals (CIs) using the 
Wilson method. The CI will be computed using SAS; the software uses the following equation 
for computing the interval: 
𝑝𝑝̂ + 𝑧𝑧𝛼𝛼/2
2
2𝑛𝑛± 𝑧𝑧𝛼𝛼/2ට(𝑝𝑝̂(1 −𝑝𝑝̂) + 𝑧𝑧𝛼𝛼/2
2
/4𝑛𝑛)/𝑛𝑛
1 + 𝑧𝑧𝛼𝛼/2
2
/4𝑛𝑛
 
Relevant Output 
Table 14.2.1.1 
Objective Response Rate Primary Efficacy Analysis (Efficacy Evaluable 
Population) 
Listing 16.2.6.1 
Overall Disease Response 
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5.4.2. 
Secondary Efficacy Analyses 
The following parameters will be analyzed by dose level and overall in both the EE and Safety 
Populations.  
• Best overall response – The number and percentage of patients in each response category 
will be summarized. 
• Percent and absolute change from baseline in quantitative serum levels of monoclonal and 
total IgM – Descriptive statistics, including change over time (i.e. percent change from 
baseline and absolute change from baseline) will be presented by dose group and overall for 
scheduled visits using central laboratory results. Only patients with a baseline value that is 
before the first dose of study treatment will be included in the change from baseline 
calculations. Local and central IgM values will be listed separately. 
Relevant Output 
Table 14.2.1.2A 
Summary of Best Overall Response (Efficacy Evaluable Population) 
Table 14.2.1.2B 
Summary of Best Overall Response (Safety Population) 
Table 14.2.2.1A 
Percent Change from Baseline in Quantitative Serum Levels of 
Monoclonal and Total IgM by Scheduled Visit (Efficacy Evaluable 
Population) 
Table 14.2.2.1B 
Percent Change from Baseline in Quantitative Serum Levels of 
Monoclonal and Total IgM by Scheduled Visit (Safety Population) 
Table 14.2.2.2A 
Absolute Change from Baseline in Quantitative Serum Levels of 
Monoclonal and Total IgM by Scheduled Visit (Efficacy Evaluable 
Population) 
Table 14.2.2.2B 
Absolute Change from Baseline in Quantitative Serum Levels of 
Monoclonal and Total IgM by Scheduled Visit (Safety Population) 
Listing 16.2.6.1 
Overall Disease Response 
Listing 16.2.6.2 
Disease Response by Visit 
Listing 16.2.6.3A 
Disease Assessment – Part 1: Lymphadenopathy and Hepatomegaly 
Listing 16.2.6.3B 
Disease Assessment – Part 2: Splenomegaly 
Listing 16.2.6.4 
Immunoglobulin (IgM) Results 
Listing 16.2.6.5A 
Central Tumor Laboratory Assessments – Part 1: Electrophoresis and 
Protein Densitometry 
Listing 16.2.6.5B 
Central Tumor Laboratory Assessments – Part 2: Serum and Urine 
Assessments 
Listing 16.2.6.6  
Local Tumor Laboratory Assessments  
5.4.3. 
Exploratory Analyses 
The following investigational factors will be presented both globally across all cohorts and by 
dose level. 
• Presence or absence of MyD88 L265P and CXCR4 mutations in tumor cells with regard to 
disease status– the summary of best overall response will be repeated by mutation status 
(present or absent) for both MyD88 L265P and CXCR4 mutations in the EE Population. 
• Serum cytokine levels – Descriptive statistics, including absolute change from baseline will 
be presented by scheduled visit for all cytokines in the EE and Safety Populations. The 
median value at each scheduled visit (excluding EOT and EOS) will be plotted by treatment 
group with standard error bars. 
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• Hemoglobin and platelets – Descriptive statistics, including absolute change from baseline 
in hemoglobin and platelets will be presented for patients who have not been transfused 
during the course of the study by scheduled visit (excluding EOT and EOS) in the EE 
Population, using central laboratory results. 
Note: Patients with transfusion will be identified by concomitant medications with an ATC 
of “Blood and Related Products.” For summary of hemoglobin, all patients with any 
medication where ATC = “Blood and Related Products,” with the exception of the preferred 
term of “Platelets,” will be excluded; for the platelet analysis, all patients with any 
medication where ATC = “Blood and Related Products” and preferred term of “Platelets” 
will be excluded. 
• Immunogenicity and NF-ĸB results will be listed. 
Additional exploratory analysis may occur. All efficacy data will be provided in data listings.  
Relevant Output 
Table 14.2.3.1 
Exploratory Efficacy Analysis: Summary of Best Overall Response by 
MyD88 and CXCR4 Mutation Status (Efficacy Evaluable Population) 
Table 14.2.4.1A 
Summary of Actual Value and Absolute Change from Baseline in Serum 
Cytokine Levels by Scheduled Visit (Efficacy Evaluable Population)  
Figure 14.2.4.1A 
Median Serum Cytokine Levels by Dose Group and Scheduled Visit 
(Efficacy Evaluable Population) 
Table 14.2.4.1B 
Summary of Actual Value and Absolute Change from Baseline in Serum 
Cytokine Levels by Scheduled Visit (Safety Population) 
Figure 14.2.4.1B 
Median Serum Cytokine Levels by Dose Group and Scheduled Visit 
(Safety Population) 
Table 14.2.4.2 
Summary of Actual Value and Absolute Change from Baseline in 
Hemoglobin and Platelets in Patients Without Transfusions During the 
Study by Scheduled Visit (Efficacy Evaluable Population)  
Listing 16.2.4.6 
MyD88 L265P and CXCR4 Mutation Status 
Listing 16.2.6.7 
Central Efficacy Laboratory Assessments: Hemoglobin and Platelets  
Listing 16.2.6.8 
Central Efficacy Laboratory Assessments: Serum NF-ĸB 
Listing 16.2.6.9 
Immunogenicity Results: Anti-IMO-8400 Antibodies 
Listing 16.2.6.10A 
Serum Cytokines Test – Part 1 
Listing 16.2.6.10B 
Serum Cytokines Test – Part 2 
Listing 16.2.6.10C 
Serum Cytokines Test – Part 3 
Listing 16.2.6.10D 
Serum Cytokines Test – Part 4 
Listing 16.2.6.11 
Bone Marrow Biopsy Results 
5.5. 
Pharmacokinetic Analyses 
All plasma concentration data and parameter estimates will be described in a separate PK SAP 
and report.  
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6. 
CHANGES TO PLANNED ANALYSES 
Protocol Section 12.2 describes a Safety/Intent-to-treat (ITT) Population and a Per-protocol (PP) 
Population for analysis. Section 2.1 of this document updates the title of the Safety/ITT 
Population to the Safety Population. The PP Population is not included in this document, and all 
efficacy analyses will be done on the EE Population, with select efficacy analyses also repeated 
on the Safety Population.  
Protocol Section 12.5 describes the exploratory analysis of presence or absence of MyD88 
L265P mutation in tumor cells. Section 2.2.5.2 of this document also includes an analysis of 
CXCR4 mutation.  
Following an interim analysis to present the study results at the 2015 American Society of 
Hematology, the protocol was amended to explore two additional dose escalations since dose-
limiting toxicity was not apparent. The last dosing cohort of 3.6 mg/kg/wk was never enrolled, 
however, as the Sponsor closed the trial prior to its scheduled opening. As a result, the efficacy 
objectives were reduced in scope substantially. Specifically, the following parameters and 
analyses described in Protocol Sections 12.4.1.2 and 12.5 are not included in this document:  
• Secondary endpoints of time-to-progression, progression-free survival, and time to best 
observed response 
• Secondary analysis of IgM data using a repeated measures mixed model 
• Exploratory analyses of NF-κB inhibition and serum levels of antibody to IMO-8400 with 
regard to disease status 
Regarding updates in safety parameters, Protocol Section 12.3 describes a time-to-event analysis 
for ISRs that is not included in this document. 
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7. 
REFERENCES 
 
Dimopoulos MA, Gertz, MA, Kastritis E, et al. Update on Treatment Recommendations from 
the Fourth International Workshop on Waldenström’s Macroglobulinemia. J Clin Oncol. 
2008; 27: 1-8. 
 
Kimby E, Treon SP, Anagnostopoulos A, et al. Update on Recommendations for Assessing 
Response from the Third International Workshop on Waldenström’s Macroglobulinemia. 
Clin Lymphoma & Myeloma. 2006; 6: 380-383. 
 
Lim K-H, Barton GM, Staudt LM. Oncogenic MYD88 mutants require Toll-like receptors. 
Amer Assoc Cancer Res, 2013 Annual Meeting, Abstract 2332. 
 
Owen RG, Kyle RA, Stone MJ, et al. Response Assessment in Waldenström’s 
Macroglobulinemia: update from the VIth International Workshop. Br J Haematology 2012; 
160:171-176. 
 
Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s 
macroglobulinemia. N Engl J Med. 2012;367(9):826–833. 
 
Young RM, Staudt LM. Targeting pathologic B cell receptor signaling in lymphoid 
malignancies. Nature Rev Drug Discovery. 2013; 12:229-243. 
 
 
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8. 
CLINICAL STUDY REPORT APPENDICES 
8.1. 
List of Statistical Tables, Figures, and Listings to be Generated 
Table 14.0.1  Treatment Codes Applicable to Tables and Listings ....................................... 40 
Table 14.1.1.1  Patient Enrollment and Disposition ............................................................... 41 
Table 14.1.2.1  Demographic Characteristics (Safety Population) ........................................ 42 
Table 14.1.2.2  Baseline Characteristics (Safety Population)................................................. 43 
Table 14.1.3.1  Disease History and Baseline Disease Characteristics (Safety Population) 44 
Table 14.1.4.1  Prior Treatments (Safety Population) ............................................................ 45 
Table 14.1.5.1  Baseline Waldenström’s Macroglobulinemia Symptoms (Safety Population)
.......................................................................................................................................... 47 
Table 14.2.1.1  Objective Response Rate Primary Efficacy Analysis (Efficacy Evaluable 
Population)...................................................................................................................... 48 
Table 14.2.1.2A  Summary of Best Overall Response (Efficacy Evaluable Population) ..... 49 
Table 14.2.1.2B  Summary of Best Overall Response (Safety Population) ........................... 49 
Table 14.2.2.1A  Percent Change from Baseline in Quantitative Serum Levels of 
Monoclonal and Total IgM by Scheduled Visit (Efficacy Evaluable Population) ... 50 
Table 14.2.2.1B  Percent Change from Baseline in Quantitative Serum Levels of 
Monoclonal and Total IgM by Scheduled Visit (Safety Population) ......................... 50 
Table 14.2.2.2A  Absolute Change from Baseline in Quantitative Serum Levels of 
Monoclonal and Total IgM by Scheduled Visit (Efficacy Evaluable Population) ... 51 
Table 14.2.2.2B  Absolute Change from Baseline in Quantitative Serum Levels of 
Monoclonal and Total IgM by Scheduled Visit (Safety Population) ......................... 51 
Table 14.2.3.1  Exploratory Efficacy Analysis: Summary of Best Overall Response by 
MyD88 and CXCR4 Mutation Status (Efficacy Evaluable Population) ................... 52 
Table 14.2.4.1A  Summary of Actual Value and Absolute Change from Baseline in Serum 
Cytokine Levels by Scheduled Visit (Efficacy Evaluable Population) ...................... 53 
Figure 14.2.4.1A  Median Serum Cytokine Levels by Dose Group and Scheduled Visit 
(Efficacy Evaluable Population) ................................................................................... 53 
Table 14.2.4.1B  Summary of Actual Value and Absolute Change from Baseline in Serum 
Cytokine Levels by Scheduled Visit (Safety Population) ........................................... 53 
Figure 14.2.4.1B  Median Serum Cytokine Levels by Dose Group and Scheduled Visit 
(Safety Population)......................................................................................................... 53 
Table 14.2.4.2  Summary of Actual Value and Absolute Change from Baseline in 
Hemoglobin and Platelets in Patients Without Transfusions During the Study by 
Scheduled Visit (Efficacy Evaluable Population)........................................................ 54 
Table 14.3.1.1  Summary of Treatment-Emergent Adverse Events (Safety Population) .... 55 
Table 14.3.1.2  Incidence of Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term (Safety Population) ............................................... 56 
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Table 14.3.1.3  Incidence of Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term and Strongest Relationship to Study Drug (Safety 
Population)...................................................................................................................... 57 
Table 14.3.1.4  Incidence of Non-Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term (Safety Population) ................ 58 
Table 14.3.1.5  Incidence of Serious Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term (Safety Population) ................................. 59 
Table 14.3.1.6  Incidence of Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term and by Highest Grade (Safety Population) ........ 60 
Table 14.3.1.7  Incidence of Dose-Limiting Toxicity Adverse Events by MedDRA System 
Organ Class and Preferred Term (Safety Population) ............................................... 61 
Table 14.3.1.8  Incidence of Observed Local Injection Site Reactions by Worst Grade Post-
Baseline (Safety Population) ......................................................................................... 62 
Table 14.3.1.9  Incidence of Observed Local Injection Site Reactions by Worst Grade and 
Scheduled Visit (Safety Population) ............................................................................. 63 
Table 14.3.2.1  Listing of Adverse Events Leading to Death ................................................. 64 
Table 14.3.2.2  Listing of Serious Adverse Events .................................................................. 65 
Table 14.3.2.3  Listing of Dose Limiting Toxicities ................................................................. 66 
Table 14.3.2.4  Listing of Premature Treatment Discontinuations Due to Adverse Events 67 
Table 14.3.5.1  Study Drug Exposure (Safety Population) ..................................................... 68 
Table 14.3.5.2A  Summary and Change from Baseline for Hematology Parameters by 
Scheduled Visit and Dose Group (Safety Population) ................................................ 69 
Table 14.3.5.2B  Summary and Change from Baseline for Chemistry Parameters by 
Scheduled Visit and Dose Group (Safety Population) ................................................ 69 
Table 14.3.5.2C  Summary and Change from Baseline for Coagulation Parameters by 
Scheduled Visit and Dose Group (Safety Population) ................................................ 69 
Table 14.3.5.2D  Summary and Change from Baseline for Serum Complement Parameters 
by Scheduled Visit and Dose Group (Safety Population) ........................................... 69 
Table 14.3.5.3A  Shifts from Baseline to Worst CTCAE Grade Post-Baseline in 
Hematology Parameters by Dose Group (Safety Population) ................................... 70 
Table 14.3.5.3B  Shifts from Baseline to Worst CTCAE Grade Post-Baseline in Chemistry 
Parameters by Dose Group (Safety Population) ......................................................... 70 
Table 14.3.5.3C  Shifts from Baseline to Worst CTCAE Grade Post-Baseline in 
Coagulation Parameters by Dose Group (Safety Population) ................................... 70 
Table 14.3.5.4  Summary and Change from Baseline for Vital Signs by Scheduled Visit and 
Dose Group (Safety Population) ................................................................................... 71 
Table 14.3.5.5  Summary and Change from Baseline for Electrocardiogram Results by 
Scheduled Visit and Dose Group (Safety Population) ................................................ 72 
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Table 14.3.5.6  Categorical Summary of QTcF Interval by Dose Group (Safety Population)
.......................................................................................................................................... 73 
Table 14.3.5.7  Shifts in QTcF Interval from Baseline by Scheduled Visit and Dose Group 
(Safety Population)......................................................................................................... 74 
Table 14.3.5.8  Shifts in Heart Rate Category from Baseline to Greatest and Lowest Post-
Baseline Values by Dose Group (Safety Population) .................................................. 75 
Table 14.3.5.9  Concomitant Medications (Safety Population) .............................................. 76 
Listing 16.0.1  System Organ Class Abbreviations ................................................................. 78 
Listing 16.2.1.1  Patient Disposition ......................................................................................... 79 
Listing 16.2.1.2  End of Treatment (EOT) Visit Status .......................................................... 80 
Listing 16.2.1.3  End of Study (EOS) Visit Status ................................................................... 81 
Listing 16.2.2.1  Listing of Inclusion/Exclusion Criteria Not Met ......................................... 82 
Listing 16.2.2.2  Protocol Deviations ........................................................................................ 83 
Listing 16.2.3.1  Study Populations .......................................................................................... 84 
Listing 16.2.4.1  Demographic Characteristics ....................................................................... 85 
Listing 16.2.4.2  Medical History .............................................................................................. 86 
Listing 16.2.4.3  Waldenström’s Macroglobulinemia Disease History ................................. 87 
Listing 16.2.4.4  Prior Waldenström’s Macroglobulinemia Therapy ................................... 88 
Listing 16.2.4.5  Baseline Waldenström’s Macroglobulinemia Symptoms........................... 89 
Listing 16.2.4.6  MyD88 L265P and CXCR4 Mutation Status .............................................. 90 
Listing 16.2.5.1  Study Drug Exposure .................................................................................... 91 
Listing 16.2.6.1  Overall Disease Response .............................................................................. 92 
Listing 16.2.6.2  Disease Response by Visit .............................................................................. 93 
Listing 16.2.6.3A  Disease Assessment – Part 1: Lymphadenopathy and Hepatomegaly ... 94 
Listing 16.2.6.3B  Disease Assessment – Part 2: Splenomegaly ............................................. 95 
Listing 16.2.6.4  Immunoglobulin (IgM) Results .................................................................... 96 
Listing 16.2.6.5A  Central Tumor Laboratory Assessments – Part 1: Electrophoresis and 
Protein Densitometry ..................................................................................................... 97 
Listing 16.2.6.5B  Central Tumor Laboratory Assessments – Part 2: Serum and Urine 
Assessments .................................................................................................................... 98 
Listing 16.2.6.6  Local Tumor Laboratory Assessments ........................................................ 99 
Listing 16.2.6.7  Central Efficacy Laboratory Assessments: Hemoglobin and Platelets .. 100 
Listing 16.2.6.8  Central Efficacy Laboratory Assessments: Serum NF-ĸB ...................... 101 
Listing 16.2.6.9  Immunogenicity Results: Anti-IMO-8400 Antibodies .............................. 102 
Listing 16.2.6.10A  Serum Cytokines Test – Part 1 .............................................................. 103 
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Listing 16.2.6.10B  Serum Cytokines Test – Part 2............................................................... 103 
Listing 16.2.6.10C  Serum Cytokines Test – Part 3 .............................................................. 103 
Listing 16.2.6.10D  Serum Cytokines Test – Part 4 .............................................................. 103 
Listing 16.2.6.11  Bone Marrow Biopsy Results .................................................................... 104 
Listing 16.2.7.1  Adverse Events by Patient and MedDRA System Organ Class / Preferred 
Term .............................................................................................................................. 105 
Listing 16.2.7.2  Adverse Events by MedDRA System Organ Class and Preferred Term 106 
Listing 16.2.7.3  Glossary of Adverse Event Verbatim Terms by MedDRA System Organ 
Class, Preferred Term, and Patient............................................................................ 107 
Listing 16.2.7.4  Injection Site Reaction Assessments .......................................................... 108 
Listing 16.2.7.5  Patient Reported Injection Site Reactions ................................................. 109 
Listing 16.2.7.6  Investigator Observed Injection Site Reactions ........................................ 110 
Listing 16.2.8.1A  Central Laboratory Results: Hematology – Part 1 ................................ 111 
Listing 16.2.8.1B  Central Laboratory Results: Hematology – Part 2 ................................ 112 
Listing 16.2.8.1C  Local Laboratory Results: Hematology – Part 1 ................................... 113 
Listing 16.2.8.1D  Local Laboratory Results: Hematology – Part 2 ................................... 113 
Listing 16.2.8.2A  Central Laboratory Results: Chemistry – Part 1 .................................. 113 
Listing 16.2.8.2B  Central Laboratory Results: Chemistry – Part 2 ................................... 113 
Listing 16.2.8.2C  Central Laboratory Results: Chemistry – Part 3 .................................. 113 
Listing 16.2.8.2D  Local Laboratory Results: Chemistry – Part 1 ...................................... 113 
Listing 16.2.8.2E  Local Laboratory Results: Chemistry – Part 2 ...................................... 113 
Listing 16.2.8.2F  Local Laboratory Results: Chemistry – Part 3 ...................................... 113 
Listing 16.2.8.3A  Central Laboratory Results: Urinalysis – Part 1 ................................... 113 
Listing 16.2.8.3B  Central Laboratory Results: Urinalysis – Part 2 ................................... 113 
Listing 16.2.8.3C  Central Laboratory Results: Urinalysis – Part 3 ................................... 113 
Listing 16.2.8.3D  Central Laboratory Results: Urinalysis – Part 4 ................................... 113 
Listing 16.2.8.3E  Central Laboratory Results: Urinalysis – Part 5 ................................... 113 
Listing 16.2.8.3F  Local Laboratory Results: Urinalysis – Part 1 ....................................... 113 
Listing 16.2.8.3G  Local Laboratory Results: Urinalysis – Part 2 ...................................... 113 
Listing 16.2.8.3H  Local Laboratory Results: Urinalysis – Part 3 ...................................... 113 
Listing 16.2.8.4A  Central Laboratory Results: Coagulation .............................................. 113 
Listing 16.2.8.4B  Local Laboratory Results: Coagulation .................................................. 113 
Listing 16.2.8.5A  Central Laboratory Results: Serum Complement ................................. 113 
Listing 16.2.8.5B  Local Laboratory Results: Serum Complement .................................... 113 
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Listing 16.2.8.6  Local Laboratory Results: Cryoglobulins ................................................. 113 
Listing 16.2.8.7  Local Laboratory Results: Cold Agglutinins ............................................ 113 
Listing 16.2.8.8  Laboratory Results: Serology ..................................................................... 114 
Listing 16.2.8.9  Pregnancy Test Results................................................................................ 115 
Listing 16.2.9.1  Vital Signs ..................................................................................................... 116 
Listing 16.2.9.2  Physical Examination Findings .................................................................. 117 
Listing 16.2.9.3  Eastern Cooperative Oncology Group (ECOG) Performance Status .... 118 
Listing 16.2.9.4  12-Lead Electrocardiogram Interval and Overall Assessment ............... 119 
Listing 16.2.9.5  Concomitant Medications ........................................................................... 120 
 
 
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8.2. 
Statistical Table and Figure Shells 
The following statistical tables and figures will be produced.
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Protocol 8400-401 
Table 14.0.1 
 
Treatment Codes Applicable to Tables and Listings 
 
Treatment Code 
Treatment Description 
0.6 mg/kg once weekly 
IMO-8400 at 0.6 mg/kg once weekly dosing 
1.2 mg/kg once weekly 
IMO-8400 at 1.2 mg/kg once weekly dosing 
1.2 mg/kg twice weekly  
IMO-8400 at 1.2 mg/kg twice weekly dosing  
2.4 mg/kg once weekly 
IMO-8400 at 2.4 mg/kg once weekly dosing 
3.6 mg/kg once weekly 
IMO-8400 at 3.6 mg/kg once weekly dosing 
Total  
Pooled IMO-8400 dosing groups 
 
Note: Dosing is based on body weight. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Only include dose groups that have at least 1 patient enrolled. Applicable to all tables.  
 
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Confidential 
Page 1 of x 
Protocol 8400-401 
Table 14.1.1.1 
 
Patient Enrollment and Disposition 
 
Disposition 
Sta-
tistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once 
weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
Total Number of Patients Enrolled [1] 
n  
xx 
xx 
xx 
xx 
xx 
xx 
Study Populations 
 
 
 
 
 
 Safety [2] 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 Efficacy Evaluable (EE)[3] 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Discontinued Treatment 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Primary Reason for Treatment 
Discontinuation from EOT [4] 
 
 
 
 
 
 
 
 DLT event 
 Disease Progression 
 Completion of 24 Weeks Treatment 
 AE, other than DLT 
 Withdrawal of Consent 
 Lost to Follow-Up 
 Study Terminated by Sponsor 
 Other 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Prematurely Discontinued Treatment [5] 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Primary Reason for Premature Treatment 
Discontinuation from EOS [6] 
 
 
 
 
 
 
 
 Disease Progression 
 AE, related to study treatment 
 AE, unrelated to study treatment 
 Non-compliance 
 Lost to Follow-Up 
 Physician Decision 
 Study Terminated by Sponsor 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Note: AE = Adverse Event. DLT = Dose-Limiting Toxicity. EOT = End of Treatment. EOS = End of Study. Unless otherwise noted, percentage 
is based on total number of patients enrolled (treated). 
[1] Enrolled: Patients who received at least one dose of study medication 
[2] All patients who received at least one dose of the study treatment  
[3] All patients who completed ≥1 cycle of therapy or those who discontinued due to progressive disease or DLT 
[4] Percentages based on the number of patients who have discontinued treatment.  
[5] Prematurely Discontinued Treatment: Patients who discontinued treatment prior to 24 weeks 
[6] Percentage based on the number of patients who have prematurely discontinued treatment.  
Reference Listings: 16.2.1.1, 16.2.3.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
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Confidential 
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Protocol 8400-401 
Table 14.1.2.1 
 
Demographic Characteristics (Safety Population) 
 
Parameter 
Statistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total  
(N=xx) 
Age (years) [1] 
 
 
 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x 
(xx.xx) 
xx.x 
xx.x,xx.x 
Ethnicity  
 
Hispanic/Latino 
 
Not Hispanic/Latino 
 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
Race  
 
American Indian  
 
or Alaska Native 
 
Asian 
 
Black 
 
Native Hawaiian or  
 
Other Pacific Islander 
 
White 
 
Other 
 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
Sex  
 
Male  
 
Female  
 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
[1] Age calculated based on date of informed consent. 
Reference Listing: 16.2.4.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
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Confidential 
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Protocol 8400-401 
Table 14.1.2.2 
 
Baseline Characteristics (Safety Population) 
 
Parameter 
Statistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total  
(N=xx) 
Baseline Height (cm) 
 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x 
(xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Baseline Weight (kg) 
 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x 
(xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Baseline BMI (kg/m2) [1] 
 
 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x 
(xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Baseline ECOG Performance 
Status [2] 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
MyD88 Mutation Status
 
Present 
 
Absent 
 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
CXCR4 Mutation Status
 
Present 
 
Absent 
 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
[1] Body Mass Index = Weight (kg)/(Height (m))2. 
[2] ECOG = Eastern Cooperative Oncology Group. 0 = Fully active, able to carry on all pre-disease performance without restriction. 1 = 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. 2 = 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours. 3 
= Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. 4 = Completely disabled. 
Reference Listings: 16.2.4.3, 16.2.4.6, 16.2.9.1, 16.2.9.3 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Include rows for Unknown and Missing for mutation status if needed.  
 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.1.3.1 
 
Disease History and Baseline Disease Characteristics (Safety Population) 
 
Parameter 
Statistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
Time Since WM Diagnosis 
(yrs) [1] 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
Baseline IPSSWM  
 
Low 
 
Intermediate 
 
High 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x)  
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x)  
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x)  
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x)  
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x)  
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x)  
xx (xx.x) 
Baseline Total IgM 
(mg/dL) 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
Baseline Monoclonal IgM 
(g/dL) 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
Baseline Hemoglobin 
(g/dL) 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
Baseline Platelet Count 
(K/cu mm) 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
Baseline Beta-2 
Microglobulin (mg/dL) 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
Note: IPSSWM = International Prognostic Scoring System for WM. Central laboratory results are presented.  
[1] Time from WM diagnosis to date of first dose of study drug. 
Reference Listings: 16.2.4.3, 16.2.6.5A, 16.2.6.5B, 16.2.6.6 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Verify units for the laboratory parameters. Use central results for laboratory parameters. See SAP Section 4.10 for 
handing of missing/partial dates for calculation of time since diagnosis.  
 
 
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Page 1 of 2 
Protocol 8400-401 
Table 14.1.4.1 
 
Prior Treatments (Safety Population) 
 
Parameter 
Statistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
Received at Least 1 Prior 
Therapy 
 
Agent/Treatment [1] 
 
 
Rituximab 
 
 
Bortezomib  
 
 
 
Cyclophosphamide 
 
 
Dexamethasone 
 
 
Vincristine 
 
 
Prednisone 
 
 
Fludarabine 
 
 
Cladribine 
 
 
Experimental [2] 
 
 
Ibrutinib 
 
 
Leukeran 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Best Overall Response [3] 
 
Complete Response (CR) 
 
Very Good Partial Response 
 
 
(VGPR) 
 
Partial Response (PR) 
 
Minor Response (MR) 
 
Stable Disease (SD) 
 
Progressive Disease (PD) 
 
Not Evaluable 
 
Delayed Response 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
  
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: AE = Adverse Event 
[1] Agent/Treatment categorized by clinical review. Only select treatments are summarized. 
[2] Experimental treatments include KPT-330 and AVILA 292.  
[3] Percentages based on number that received at least 1 prior therapy.  
[4] Time from end of prior therapy to date of first dose of IMO-8400. 
Reference Listing: 16.2.4.4 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: See page 2. 
 
 
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Confidential 
Page 2 of 2 
Protocol 8400-401 
Table 14.1.4.1 
 
Prior Treatments (Safety Population 
 
Parameter 
Statistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
Reason for Discontinuation [3] 
 
Failure to respond 
 
Treatment related AE 
 
Not treatment related AE 
 
Patient Non-Compliance 
 
Physician Decision 
 
Unknown 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of Prior Therapies 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
Number of Prior Therapies 
Categories 
 
1 Prior Therapy 
 
2 Prior Therapies 
 
3 Prior Therapies 
 
4+ Prior Therapies 
 
 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of Days Since Most 
Recent Prior Therapy [4] 
n 
Mean (SD) 
Median 
Min,Max 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
xx 
xx.x (xx.xx) 
xx.xx 
xx, xx 
Note: AE = Adverse Event 
[1] Agent/Treatment categorized by clinical review. Only select treatments are summarized. 
[2] Experimental treatments include KPT-330, AVILA 292, and TRU-16.  
[3] Percentages based on number that received at least 1 prior therapy.  
[4] Time from end of prior therapy to date of first dose of IMO-8400. 
Reference Listing: 16.2.4.4 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Number of days since Most Recent Prior Therapy = (date of first dose – end date of most recent prior therapy)  
Update the experimental treatments in the footnote to include all experimental treatments at the time of the analysis. See SAP Section 
4.10 for handing of missing/partial dates.  
  
 
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Page x of y 
Protocol 8400-401 
Table 14.1.5.1 
 
Baseline Waldenström’s Macroglobulinemia Symptoms (Safety Population) 
 
Baseline Symptom 
Statistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total  
(N=xx) 
Bleeding Events  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Fatigue  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Anemia  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Thrombocytopenia  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Leukemia/Neutropenia  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Fever  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Hyperviscosity  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Neuropathy  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Lymphadenopathy 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Weight Loss  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Headache 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Night Sweats  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Vision Changes  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Other 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reference Listing: 16.2.4.5 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
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Statistical Analysis Plan 
 
Page 48 of 124 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.1.1 
 
Objective Response Rate Primary Efficacy Analysis (Efficacy Evaluable Population) 
 
Parameter 
Statistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total (N=xx) 
Objective Response Rate  
(CR/VGPR/PR/MR) 
n (%) 
90%CI [1] 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
xx (xx.x) 
x.xxx,x.xxx 
Note: CR = Complete response. VGPR = Very good partial response. PR = Partial response. MR = Minor response. 
[1] CI = Confidence interval. Confidence intervals calculated using Wilson’s method. 
Reference Listing: 16.2.6.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
190-289


Statistical Analysis Plan 
 
Page 49 of 124 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.1.2A 
 
Summary of Best Overall Response (Efficacy Evaluable Population) 
 
Parameter 
Sta-
tistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total (N=xx) 
Best Overall Response 
 
Complete response (CR) 
 
Very good partial response (VGPR) 
 
Partial response (PR) 
 
Minor response (MR) 
 
Stable disease (SD) 
 
Progressive disease (PD) 
 
Not evaluable 
 
Delayed response 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reference Listing: 16.2.6.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
Repeat for:  
Table 14.2.1.2B  Summary of Best Overall Response (Safety Population) 
 
 
 
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Statistical Analysis Plan 
 
Page 50 of 124 
Protocol 8400-401, Final Version 2.0 
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Idera Pharmaceuticals, Inc. 
Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.2.2.1A 
 
Percent Change from Baseline in Quantitative Serum Levels of Monoclonal and Total IgM by Scheduled Visit (Efficacy Evaluable 
Population) 
 
Parameter: [Describe: Monoclonal IgM (g/dL)] 
Visit 
Statistic 
Value 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg once 
weekly (N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
Baseline n 
Mean (SD) 
Median 
Min,Max 
Actual Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x 
(xx.xx) 
xx.x 
xx.x,xx.x 
C1W9 
n 
Mean (SD) 
Median 
Min,Max 
Actual Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x 
(xx.xx) 
xx.x 
xx.x,xx.x 
 
n 
Mean (SD) 
Median 
Min,Max 
Percent Change 
from Baseline 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x 
(xx.xx) 
xx.x 
xx.x,xx.x 
Etc. 
 
 
 
 
 
 
Note: Baseline = the most recent laboratory assessment before the first dose of study medication. 
Reference Listing: 16.2.6.4 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Present Total IgM or Monoclonal IgM as the parameter, with the unit, using central lab results only.  
 
 
Repeat for: 
Table 14.2.2.1B  Percent Change from Baseline in Quantitative Serum Levels of Monoclonal and Total IgM by Scheduled Visit (Safety 
Population) 
   
 
 
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Statistical Analysis Plan 
 
Page 51 of 124 
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Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.2.2.2A 
 
Absolute Change from Baseline in Quantitative Serum Levels of Monoclonal and Total IgM by Scheduled Visit (Efficacy Evaluable 
Population) 
 
Parameter: [Monoclonal IgM (g/dL)] 
Visit 
Statistic 
Value 
0.6 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total (N=xx) 
Baseline n 
Mean (SD) 
Median 
Min,Max 
Actual 
Value 
xx 
xx.x 
(xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
C1W9 
n 
Mean (SD) 
Median 
Min,Max 
Actual 
Value 
xx 
xx.x 
(xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
n 
Mean (SD) 
Median 
Min,Max 
Change 
from 
Baseline 
xx 
xx.x 
(xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc. 
 
 
 
 
 
 
Note: Baseline = the most recent laboratory assessment before the first dose of study medication. 
Reference Listing: 16.2.6.4 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Present Total IgM or Monoclonal IgM as the parameter, with the unit, using central lab results only.  
 
 
Repeat for: 
Table 14.2.2.2B  Absolute Change from Baseline in Quantitative Serum Levels of Monoclonal and Total IgM by Scheduled Visit (Safety 
Population) 
  
 
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Page 52 of 124 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.2.3.1 
 
Exploratory Efficacy Analysis: Summary of Best Overall Response by MyD88 and CXCR4 Mutation Status (Efficacy Evaluable Population) 
 
Mutation 
Status 
Best Overall Response 
Sta-
tistic 
0.6 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
twice 
weekly 
(N=xx) 
2.4 mg/kg 
once 
weekly 
(N=xx) 
3.6 mg/kg 
once 
weekly 
(N=xx) 
Total 
(N=xx) 
MyD88 
Present 
 
Complete response 
Very good partial response 
Partial response 
Minor response 
Stable disease 
Progressive disease 
Not evaluable 
Delayed response 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Absent 
Complete response 
Very good partial response 
Partial response 
Minor response 
Stable disease 
Progressive disease 
Not evaluable 
Delayed response 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
CXCR4 
Present 
 
Complete response 
Very good partial response 
Partial response 
Minor response 
Stable disease 
Progressive disease 
Not evaluable 
Delayed response 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Absent 
Complete response 
Very good partial response 
Partial response 
Minor response 
Stable disease 
Progressive disease 
Not evaluable 
Delayed response 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reference Listings: 16.2.4.6, 16.2.6.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
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Page 53 of 124 
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Confidential and Proprietary 
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Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.2.4.1A 
 
Summary of Actual Value and Absolute Change from Baseline in Serum Cytokine Levels by Scheduled Visit (Efficacy Evaluable Population) 
 
Parameter: [Cytokine 1 (unit)] 
Visit 
Statistic 
Value 
0.6 mg/kg once 
weekly (N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg once 
weekly (N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total (N=xx) 
Baseline n 
Mean (SD) 
Median 
Min,Max 
Actual 
Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
C1W9 
n 
Mean (SD) 
Median 
Min,Max 
Actual 
Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
n 
Mean (SD) 
Median 
Min,Max 
Change 
from 
Baseline 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc. 
 
 
 
 
 
 
Note: Baseline = the most recent laboratory assessment before the first dose of study medication. 
Reference Listings: 16.2.6.10A, 16.2.6.10B, 16.2.6.10C, 16.2.6.10D 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: For the figures, present the median value for each treatment group at each visit (excluding EOT and EOS), and 
include standard error bars.  
 
Figure:  
Figure 14.2.4.1A  Median Serum Cytokine Levels by Dose Group and Scheduled Visit (Efficacy Evaluable Population) 
 
 
Repeat for: 
Table 14.2.4.1B  Summary of Actual Value and Absolute Change from Baseline in Serum Cytokine Levels by Scheduled Visit (Safety 
Population) 
Figure 14.2.4.1B  Median Serum Cytokine Levels by Dose Group and Scheduled Visit (Safety Population) 
 
 
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Statistical Analysis Plan 
 
Page 54 of 124 
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Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.2.4.2 
 
Summary of Actual Value and Absolute Change from Baseline in Hemoglobin and Platelets in Patients Without Transfusions During the 
Study by Scheduled Visit (Efficacy Evaluable Population) 
 
Parameter: [Parameter (unit)] 
Visit 
Statistic 
Value 
0.6 mg/kg once 
weekly (N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg once 
weekly (N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total (N=xx) 
Baseline n 
Mean (SD) 
Median 
Min,Max 
Actual 
Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
C1W9 
n 
Mean (SD) 
Median 
Min,Max 
Actual 
Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
n 
Mean (SD) 
Median 
Min,Max 
Change 
from 
Baseline 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc. 
 
 
 
 
 
 
Note: Baseline = the most recent laboratory assessment before the first dose of study medication. 
Reference Listing: 16.2.6.6 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
Programming note: Use central labs only.  
 
 
196-289


Statistical Analysis Plan 
 
Page 55 of 124 
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Protocol 8400-401 
Table 14.3.1.1 
 
Summary of Treatment-Emergent Adverse Events (Safety Population) 
 
Parameter 
Sta-
tistic 
0.6 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
twice 
weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total (N=xx) 
At Least 1 TEAE 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 Related TEAE 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 Grade >=3 TEAE 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 SAE 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 DLT 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 TEAE Leading to Death 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
At Least 1 TEAE Leading to Premature 
Treatment Discontinuation 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Note: TEAE = Treatment-Emergent Adverse Event. SAE = Serious Adverse Event. DLT = Dose Limiting Toxicity.  
 
Related = Adverse events identified by the Investigator as probably or possibly related to the study drug, or with a missing 
relationship.   
Reference Listing: 16.2.7.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
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Statistical Analysis Plan 
 
Page 56 of 124 
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Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.1.2 
 
Incidence of Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term (Safety Population) 
 
MedDRA System Organ Class / 
Preferred Term 
Sta-
tistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
At Least 1 TEAE 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 2 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 3 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Etc. 
 
 
 
 
 
 
 
 
Note: TEAE = Treatment-Emergent Adverse Event. Adverse Events coded per MedDRA Version 16.1. If a patient experienced more than one 
episode of an adverse event, that patient is counted once within a System Organ Class and Preferred Term.              
Reference Listing: 16.2.7.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
 
198-289


Statistical Analysis Plan 
 
Page 57 of 124 
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Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.3.1.3 
 
Incidence of Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term and Strongest Relationship to Study 
Drug (Safety Population) 
 
MedDRA System Organ 
Class/  
Preferred Term 
Relation-
ship  
Sta-
tistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice 
weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
At Least 1 TEAE 
Related 
Not-Related 
n (%) 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
SOC 1 
 
 
Preferred Term 1 
 
 
Preferred Term 2 
 
 
 
Etc. 
Related 
Not-Related 
Related 
Not-Related 
Related 
Not-Related 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Etc. 
 
 
 
 
 
 
 
 
Note: TEAE = Treatment-Emergent Adverse Event. Adverse Events coded per MedDRA Version 16.1.  
 
Drug related adverse events are those which are identified by the investigator as probably or possibly related to the study drug, 
or with a missing relationship, and not related adverse events are those which are unlikely and not related to the study drug. If a 
patient experienced more than one episode of an adverse event, that patient is counted once within a System Organ Class and 
Preferred Term by the strongest relationship to study drug.  
Reference Listing: 16.2.7.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
  
 
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Statistical Analysis Plan 
 
Page 58 of 124 
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Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.1.4 
 
Incidence of Non-Serious Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term (Safety Population) 
 
MedDRA System Organ Class  
 
Preferred Term 
Statistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
At Least 1 Non-serious TEAE 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 2 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Etc. 
 
 
 
 
 
 
 
Note: TEAE = Treatment-Emergent Adverse Event. Adverse Events coded per MedDRA Version 16.1. If a patient experienced more than one 
episode of an adverse event, that patient is counted once within a System Organ Class and Preferred Term.              
Reference Listing: 16.2.7.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
200-289


Statistical Analysis Plan 
 
Page 59 of 124 
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Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.1.5 
 
Incidence of Serious Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term (Safety Population) 
 
MedDRA System Organ Class  
 
Preferred Term 
Statistic 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
At Least 1 Serious TEAE 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 2 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Etc. 
 
 
 
 
 
 
 
Note: TEAE = Treatment-Emergent Adverse Event. Adverse Events coded per MedDRA Version 16.1. If a patient experienced more than one 
episode of an adverse event, that patient is counted once within a System Organ Class and Preferred Term.              
Reference Listing: 16.2.7.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
201-289


Statistical Analysis Plan 
 
Page 60 of 124 
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21 April 2017 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.3.1.6 
 
Incidence of Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term and by Highest Grade 
(Safety Population) 
 
 
 
0.6 mg/kg once weekly (N=xx) 
 
1.2 mg/kg once weekly (N=xx) 
MedDRA System Organ Class  
 
Preferred Term 
Sta-
tistic 
Grade 1 
or 2 
Grade 3 
Grade >= 
4 
Total 
 
Grade 1 
or 2 
Grade  3 
Grade >= 
4 
Total 
At Least 1 TEAE 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
Etc. 
 
 
 
 
 
 
 
 
 
 
Note: TEAE = Treatment-Emergent Adverse Event. Adverse Events coded per MedDRA Version 16.1. If a patient experienced more than one 
episode of an adverse event, that patient is counted once within a System Organ Class and Preferred Term by the highest severity.              
Reference Listing: 16.2.7.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Move onto multiple pages as needed; include all dose groups with at least one patient and total (0.6 once weekly, 
1.2 once weekly, 1.2 twice weekly, 2.4 once weekly, 3.6 once weekly, and total).  
 
202-289


Statistical Analysis Plan 
 
Page 61 of 124 
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21 April 2017 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.1.7 
 
Incidence of Dose-Limiting Toxicity Adverse Events by MedDRA System Organ Class and Preferred Term (Safety Population) 
 
MedDRA System Organ Class  
 
Preferred Term 
Statistic 
0.6 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
At Least 1 DLT 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 1 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC 2 
 
Preferred Term 1 
 
Preferred Term 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: DLT = Dose-Limiting Toxicity. Adverse Events coded per MedDRA Version 16.1. If a patient experienced more than one episode of an 
adverse event, that patient is counted once within a System Organ Class and Preferred Term.              
Reference Listing: 16.2.7.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
203-289


Statistical Analysis Plan 
 
Page 62 of 124 
Protocol 8400-401, Final Version 2.0 
21 April 2017 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.1.8 
 
Incidence of Observed Local Injection Site Reactions by Worst Grade Post-Baseline (Safety Population) 
 
Symptom / 
Toxicity Grade 
Statistic 
0.6 mg/kg once 
weekly (N=xx) 
1.2 mg/kg once 
weekly (N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg once 
weekly (N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
Pain 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Tenderness 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
<Repeat above format for Pruritus and Induration> 
Blister 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Blister (mm) 
 
n 
Mean (SD) 
Median 
Min,Max 
25th Percentile 
75th Percentile 
90th Percentile 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx.x 
xx.x 
xx.x 
<Repeat above format (2 rows each) for Ulceration, Erythema, and Necrosis> 
Note: In the case of multiple grades, only the worst grade post baseline is counted for each patient and symptom regardless of the 
site of injection. 
Reference Listing: 16.2.7.6 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Include higher grades if there are any to report for each symptom.   
 
204-289


Statistical Analysis Plan 
 
Page 63 of 124 
Protocol 8400-401, Final Version 2.0 
21 April 2017 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.1.9 
 
Incidence of Observed Local Injection Site Reactions by Worst Grade and Scheduled Visit (Safety Population) 
 
Visit 
Symptom / 
Toxicity Grade 
Statistic 
0.6 mg/kg once 
weekly (N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg once 
weekly (N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
Day 1 
Pain 
 
Grade 1 
 
Grade 2 
 
Grade 3
 
Grade 4  
 
Grade 5 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Tenderness 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
Grade 4  
 
Grade 5 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Etc. 
 
 
 
 
 
 
 
Day 3 
Pain 
 
Grade 1 
 
Grade 2 
 
Grade 3
 
Grade 4  
 
Grade 5 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Tenderness 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
Grade 4  
 
Grade 5 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Etc. 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
Note: In the case of multiple grades, only the worst grade at each visit is counted for each patient and symptom regardless of the 
site of injection. 
Reference Listing: 16.2.7.6 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Include all symptoms and all visits.  
 
 
205-289


Statistical Analysis Plan 
 
Page 64 of 124 
Protocol 8400-401, Final Version 2.0 
21 April 2017 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.2.1 
 
Listing of Adverse Events Leading to Death 
 
 
Dose Group:  
 
 
 
Onset 
 
End 
 
 
 
 
Patient 
Number 
SOC 
[1] 
Preferred 
Term 
Date/ 
Time 
Rel 
Day 
[2] 
 
Date/ 
Time 
Rel 
Day 
[2] 
Sever-
ity 
[3] 
SAE 
TEAE 
DLT 
Rela-
tionship 
[4] 
Action 
Taken 
with IMO-
8400 
Action 
Taken for 
AE 
Sequelae 
at 
Resolution 
 
 
 
 
 
 
 
 
 
Yes 
No 
Yes 
No 
Yes 
No 
 
 
 
Yes: 
No 
 
 
 
Note: SOC = System Organ Class. SAE = Serious adverse event. TEAE = Treatment-emergent adverse event. DLT = Dose limiting toxicity. CM 
= Concomitant medication. Adverse events coded per MedDRA version 16.1.  
[1] Refer to listing 16.0.1 for the full SOC name associated with the corresponding abbreviation.                                       
[2] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[3] 1 = Grade 1: Mild. 2 = Grade 2: Moderate. 3 = Grade 3: Marked. 4 = Grade 4: Extreme. 5 = Grade 5: Death. 
[4] Relationship to Study Drug: Prob Rel = Probably Related, Poss Rel = Possibly Related, Unlike Rel = Unlikely Related, Not Rel = Not 
related. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If sequelae at resolution, concatenate specifics (Yes: Specify sequelae). 
 
 
206-289


Statistical Analysis Plan 
 
Page 65 of 124 
Protocol 8400-401, Final Version 2.0 
21 April 2017 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.2.2 
 
Listing of Serious Adverse Events 
 
Dose Group:  
 
 
 
Onset 
 
End 
 
 
 
Patient 
Number 
SOC 
[1] 
Preferred 
Term 
Date/ 
Time 
Rel 
Day 
[2] 
 
Date/ 
Time 
Rel 
Day 
[2] 
Sever-
ity 
[3] 
TEAE 
DLT 
Rela-
tionship 
[4] 
Action 
Taken 
with IMO-
8400 
Action 
Taken for 
AE 
Sequelae 
at 
Resolution 
 
 
 
 
 
 
 
 
 
Yes 
No 
Yes 
No 
 
 
 
Yes: 
No 
 
 
 
 
 
 
 
Note: SOC = System Organ Class. SAE = Serious adverse event. TEAE = Treatment-emergent adverse event. DLT = Dose limiting toxicity. CM 
= Concomitant medication. Adverse events coded per MedDRA version 16.1.  
[1] Refer to listing 16.0.1 for the full SOC name associated with the corresponding abbreviation.                                       
[2] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[3] 1 = Grade 1: Mild. 2 = Grade 2: Moderate. 3 = Grade 3: Marked. 4 = Grade 4: Extreme. 5 = Grade 5: Death. 
[4] Relationship to Study Drug: Prob Rel = Probably Related, Poss Rel = Possibly Related, Unlike Rel = Unlikely Related, Not Rel = Not 
related. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If sequelae at resolution, concatenate specifics (Yes: Specify sequelae). 
 
 
207-289


Statistical Analysis Plan 
 
Page 66 of 124 
Protocol 8400-401, Final Version 2.0 
21 April 2017 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.2.3 
 
Listing of Dose Limiting Toxicities 
 
Dose Group:  
 
 
 
Onset 
 
End 
 
 
 
Patient 
Number 
SOC 
[1] 
Preferred 
Term 
Date/ 
Time 
Rel 
Day 
[2] 
 
Date/ 
Time 
Rel 
Day 
[2] 
Sever-
ity 
[3] 
SAE 
TEAE 
Rela-
tionship 
[4] 
Action 
Taken 
with IMO-
8400 
Action 
Taken for 
AE 
Sequelae 
at 
Resolution 
 
 
 
 
 
 
 
 
 
Yes 
No 
Yes 
No 
 
 
 
Yes: 
No 
 
 
 
 
 
 
 
Note: SOC = System Organ Class. SAE = Serious adverse event. TEAE = Treatment-emergent adverse event. DLT = Dose limiting toxicity. CM 
= Concomitant medication. Adverse events coded per MedDRA version 16.1.  
[1] Refer to listing 16.0.1 for the full SOC name associated with the corresponding abbreviation.                                       
[2] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[3] 1 = Grade 1: Mild. 2 = Grade 2: Moderate. 3 = Grade 3: Marked. 4 = Grade 4: Extreme. 5 = Grade 5: Death. 
[4] Relationship to Study Drug: Prob Rel = Probably Related, Poss Rel = Possibly Related, Unlike Rel = Unlikely Related, Not Rel = Not 
related. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If sequelae at resolution, concatenate specifics (Yes: Specify sequelae). 
 
 
208-289


Statistical Analysis Plan 
 
Page 67 of 124 
Protocol 8400-401, Final Version 2.0 
21 April 2017 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.2.4 
 
Listing of Premature Treatment Discontinuations Due to Adverse Events 
 
Dose Group:  
 
 
 
Onset 
 
End 
 
 
 
 
Patient 
Number 
SOC 
[1] 
Preferred 
Term 
Date/ 
Time 
Rel 
Day 
[2] 
 
Date/ 
Time 
Rel 
Day 
[2] 
Sever-
ity 
[3] 
SAE 
TEAE 
DLT 
Rela-
tionship 
[4] 
Action 
Taken 
with IMO-
8400 
Action 
Taken for 
AE 
Sequelae 
at 
Resolution 
 
 
 
 
 
 
 
 
 
Yes 
No 
Yes 
No 
Yes 
No 
 
 
 
Yes: 
No 
 
 
 
 
 
 
 
Note: SOC = System Organ Class. SAE = Serious adverse event. TEAE = Treatment-emergent adverse event. DLT = Dose limiting toxicity. CM 
= Concomitant medication. Adverse events coded per MedDRA version 16.1.  
[1] Refer to listing 16.0.1 for the full SOC name associated with the corresponding abbreviation.                                       
[2] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[3] 1 = Grade 1: Mild. 2 = Grade 2: Moderate. 3 = Grade 3: Marked. 4 = Grade 4: Extreme. 5 = Grade 5: Death. 
[4] Relationship to Study Drug: Prob Rel = Probably Related, Poss Rel = Possibly Related, Unlike Rel = Unlikely Related, Not Rel = Not 
related. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If sequelae at resolution, concatenate specifics (Yes: Specify sequelae). 
 
 
209-289


Statistical Analysis Plan 
 
Page 68 of 124 
Protocol 8400-401, Final Version 2.0 
21 April 2017 
 
 
Idera Pharmaceuticals, Inc. and Veristat, LLC 
Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Table 14.3.5.1 
 
Study Drug Exposure (Safety Population) 
 
Parameter 
Statistics 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total  
(N=xx) 
Cumulative Exposure (mg) [1]  
n 
Mean  
SD 
Median 
Min,Max 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
Cycles Received [2] 
 
Received <1 Cycle 
 
Received 1 Cycle 
 
Received 2 Cycles 
 
Received 3 Cycles 
 
Received 4 Cycles 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of Doses Received 
n 
Mean  
SD 
Median 
Min,Max 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
Number of Missed Doses 
n 
Mean  
SD 
Median 
Min,Max 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
xx 
xx.x  
xx.xx 
xx.x 
xx.x,xx.x 
Reason Dose Missed [3] 
 
DLT 
 
AE 
 
Visit missed 
 
DME 
 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: AE = Adverse event. DLT = Dose limiting toxicity. DME = Dose modifying event.  
[1] Cumulative exposure is the sum of all doses received, where each dose is calculated as [assigned dose (mg/kg) * volume 
administered (mL)] / concentration of 0.007 (mL/kg). 
[2] A completed cycle is defined as having received 8 weeks of treatment for that cycle.  
[3] Percentages based on number of patients that had at least one missed dose. Each patient is tallied once per reason, regardless of 
how many doses were missed for that reason. 
Reference Listing: 16.2.5.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Add “unknown” as a reason dose missed if applicable. Add more cycles if needed for cycles received.  
 
 
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Statistical Analysis Plan 
 
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Confidential 
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Protocol 8400-401 
Table 14.3.5.2A 
 
Summary and Change from Baseline for Hematology Parameters by Scheduled Visit and Dose Group (Safety Population) 
 
Parameter: [Lab Test 1 (unit)] 
Visit 
Statistic 
Value 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg once 
weekly (N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total (N=xx) 
Baseline n 
Mean (SD) 
Median 
Min,Max 
Actual Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
C1W9 
n 
Mean (SD) 
Median 
Min,Max 
Actual Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
n 
Mean (SD) 
Median 
Min,Max 
Change from 
Baseline 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc. 
 
 
 
 
 
 
 
Note: Baseline = the most recent laboratory assessment before the first dose of study medication. 
Reference Listings: 16.2.8.1A, 16.2.8.1B 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
 
Repeat for: 
Table 14.3.5.2B  Summary and Change from Baseline for Chemistry Parameters by Scheduled Visit and Dose Group (Safety Population) 
Table 14.3.5.2C  Summary and Change from Baseline for Coagulation Parameters by Scheduled Visit and Dose Group (Safety Population) 
Table 14.3.5.2D  Summary and Change from Baseline for Serum Complement Parameters by Scheduled Visit and Dose Group (Safety 
Population) 
 
Programming note: Use central labs only. Update references listings for the repeat tables.  
 
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Confidential 
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Protocol 8400-401 
Table 14.3.5.3A 
 
Shifts from Baseline to Worst CTCAE Grade Post-Baseline in Hematology Parameters by Dose Group (Safety Population) 
 
 
Worst CTC Grade Post-Baseline Results 
Laboratory 
Parameter 
Dose Group 
Baseline 
Results 
Sta-
tistic 
WNL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Missing 
Lab Test 1 
(unit) 
0.6 mg/kg once 
weekly (N=xx) 
WNL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Missing 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
1.2 mg/kg once 
weekly (N=xx) 
WNL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Missing 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Etc. 
 
 
 
 
 
 
 
 
Lab Test 2 
(unit) 
0.6 mg/kg once 
weekly (N=xx) 
WNL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Missing 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Etc. 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
Note: Baseline = the most recent laboratory assessment before the first dose of study medication. WNL = Within Normal Limit. 
Reference Listing: 16.2.8.1A, 16.2.8.1B  
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Repeat analyses for all laboratory parameters and all visits. Include all dose groups that have at least 1 patient 
and total (0.6 once weekly, 1.2 once weekly, 1.2 twice weekly, 2.4 once weekly, 3.6 once weekly, and total).  
 
Repeat for: 
Table 14.3.5.3B  Shifts from Baseline to Worst CTCAE Grade Post-Baseline in Chemistry Parameters by Dose Group (Safety Population) 
Table 14.3.5.3C  Shifts from Baseline to Worst CTCAE Grade Post-Baseline in Coagulation Parameters by Dose Group (Safety Population) 
 
Programming note: Use central labs only. Update references listings for the repeat tables.  
 
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Confidential 
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Protocol 8400-401 
Table 14.3.5.4 
 
Summary and Change from Baseline for Vital Signs by Scheduled Visit and Dose Group (Safety Population) 
 
Parameter: [VS 1 (unit)] 
 
Visit 
Statistic 
Value 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg once 
weekly (N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total (N=xx) 
Baseline n 
Mean (SD) 
Median 
Min,Max 
Actual Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
C1W9 
n 
Mean (SD) 
Median 
Min,Max 
Actual Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
n 
Mean (SD) 
Median 
Min,Max 
Change from 
Baseline 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc. 
 
 
 
 
 
 
 
Reference Listing: 16.2.9.1 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Repeat analyses for all vital sign parameters.  
  
 
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Statistical Analysis Plan 
 
Page 72 of 124 
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Confidential 
Page 1 of y 
Protocol 8400-401 
Table 14.3.5.5 
 
Summary and Change from Baseline for Electrocardiogram Results by Scheduled Visit and Dose Group (Safety Population) 
 
Parameter: [ECG 1 (unit)] 
 
Visit 
Statistic 
Value 
0.6 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
once weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg once 
weekly (N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total (N=xx) 
Baseline n 
Mean (SD) 
Median 
Min,Max 
Actual Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
C1W9 
n 
Mean (SD) 
Median 
Min,Max 
Actual Value 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
 
n 
Mean (SD) 
Median 
Min,Max 
Change from 
Baseline 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
xx 
xx.x (xx.xx) 
xx.x 
xx.x,xx.x 
Etc. 
 
 
 
 
 
 
Reference Listing: 16.2.9.4 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: Repeat for all ECG parameters; use derived QTcF for the QTc interval.  
 
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Statistical Analysis Plan 
 
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Table 14.3.5.6 
 
Categorical Summary of QTcF Interval by Dose Group (Safety Population) 
 
 
QTcF Observation 
Statistic 
0.6 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
Subjects who experienced a QTcF: 
 
 
 
 
 
 
 
>450 
>480 
>500 
 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Subjects who experienced change from  
baseline in QTcF of: 
 
>30 
 
>60 
 
 
n (%) 
n (%) 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
Reference Listing: 16.2.9.4 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Subjects may be counted in multiple categories. 
 
 
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Confidential 
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Protocol 8400-401 
Table 14.3.5.7 
 
Shifts in QTcF Interval from Baseline by Scheduled Visit and Dose Group (Safety Population) 
 
 
 
 
 
Post-Baseline Value 
Visit 
Dose Group 
Baseline Results 
Statistic 
<=450 
451-480 
481-500 
>500 
Missing 
C1W2 
0.6 mg/kg once 
weekly (N=xx) 
<=450 
451-480 
481-500 
>500 
Missing 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Baseline = the most recent assessment before the first dose of study medication. QTc calculated using Fridericia correction 
formula. 
Reference Listing: 16.2.9.4 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Include all dose groups that have at least 1 patient and total (0.6 once weekly, 1.2 once weekly, 1.2 twice weekly, 
2.4 once weekly, 3.6 once weekly, and total). 
 
 
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Statistical Analysis Plan 
 
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Confidential 
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Protocol 8400-401 
Table 14.3.5.8 
 
Shifts in Heart Rate Category from Baseline to Greatest and Lowest Post-Baseline Values by Dose Group (Safety Population) 
 
 
 
 
Greatest Post-Baseline Value 
 
Lowest Post-Baseline Value 
Dose Group 
Baseline 
Results 
Sta-
tistic 
<60 bpm 
60-100 bpm 
>100 bpm 
Missing 
 
<60 bpm 
60-100 bpm 
>100 bpm 
Missing 
0.6 mg/kg 
once weekly 
(N=xx) 
<60 bpm 
60-100 bpm 
>100 bpm 
Missing 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
1.2 mg/kg 
once weekly 
(N=xx) 
<60 bpm 
60-100 bpm 
>100 bpm 
Missing 
n (%) 
n (%) 
n (%) 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Baseline = the most recent assessment before the first dose of study medication.  
Reference Listing: 16.2.9.4 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Include all dose groups and total (0.6 once weekly, 1.2 once weekly, 1.2 twice weekly, 2.4 once weekly, 3.6 once 
weekly, and total).  
  
 
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Protocol 8400-401 
Table 14.3.5.9 
 
Concomitant Medications (Safety Population) 
 
ATC Classification 
Statistic 
0.6 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
once 
weekly 
(N=xx) 
1.2 mg/kg 
twice weekly 
(N=xx) 
2.4 mg/kg 
once weekly 
(N=xx) 
3.6 mg/kg 
once weekly 
(N=xx) 
Total 
(N=xx) 
Any Concomitant Medication 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
CM CLASS 1 
 
CM Code 1 
 
CM Code 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
CM CLASS 2 
 
CM Code 1 
 
CM Code 2 
 
Etc. 
n (%) 
n (%) 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Etc. 
 
 
 
 
 
 
 
[1] ATC = Anatomic Therapeutic Classification from WHO Drug Dictionary Q12013. 
Reference Listing: 16.2.9.5 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming Note: Repeat analyses for all CM classes and CM codes. Update drug dictionary if necessary at time of programming.  
 
  
 
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8.3. 
Data Listing Shells 
The following data listings will be produced. 
 
 
 
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Listing 16.0.1 
 
System Organ Class Abbreviations 
 
SOC 
Abbreviations 
Blood and lymphatic system disorders 
BLOOD 
Cardiac disorders 
CARD 
Congenital, familial and genetic disorders 
CONGN 
Ear and labyrinth disorders 
EAR 
Endocrine disorders 
ENDO 
Eye disorders 
EYE 
Gastrointestinal disorders 
GASTR 
General disorders and administration site conditions 
GENRL 
Hepatobiliary disorders 
HEPAT 
Immune system disorders 
IMMUN 
Infections and infestations 
INFCT 
Injury, poisoning and procedural complications 
INJUR 
Investigations 
INVST 
Metabolism and nutrition disorders 
METAB 
Musculoskeletal and connective tissue disorders 
MUSCL 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
NEOPL 
Nervous system disorders 
NERV 
Pregnancy, puerperium and perinatal conditions 
PREG 
Psychiatric disorders 
PSYCH 
Renal and urinary disorders 
RENAL 
Reproductive system and breast disorders 
REPRO 
Respiratory, thoracic and mediastinal disorders 
RESP 
Skin and subcutaneous tissue disorders 
SKIN 
Social circumstances 
SOCL 
Surgical and medical procedures 
SURG 
Vascular disorders 
VASC 
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: Verify the list of abbreviations includes all SOCs.  
 
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Protocol 8400-401 
Listing 16.2.1.1 
 
Patient Disposition 
 
Dose 
Group 
Patient 
Number 
Number of  
Cycles 
Received 
[1] 
Patient Had 
a Dose 
Level 
Reduction  
Date of 
Last 
Dose 
Rel Day 
[2] 
Primary Reason for 
Termination of 
Treatment 
Reason 
Discontinued 
Study 
Reason End of 
Study Visit 
Not Completed 
Y:  
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] A completed cycle is defined as having received 8 weeks of treatment for that cycle; 0 indicates patient completed < 1 cycle. 
[2] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: Reason discontinued taken from “Please indicate the primary reason patient did not complete all weeks” question. If 
the patient had a dose level reduction, concatenate the reduced dose level “Y: “.   
 
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Listing 16.2.1.2 
 
End of Treatment (EOT) Visit Status 
 
Dose 
Group 
Patient Number 
Date of 
Treatment 
Termination 
Rel 
Day 
[1] 
Primary Reason for 
Termination of 
Treatment 
Specifics 
Comments 
Patient Had a 
Dose Level 
Reduction  
Date 
of 
EOT 
visit 
Rel 
Day 
[1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLT event 
Disease 
Progression 
Completion of 24 
weeks treatment 
AE 
Withdrawal of 
Consent 
Lost to Follow-Up 
Study Termination 
by Sponsor 
Other 
 
 
Y:  
N 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: Primary reason for termination of treatment taken from the EOT page.  Include additional specification under 
“Specifics”. Include “Please specify DLT event”, “Please specify disease progression”, “Please specify other adverse event”, “Please 
explain all attempts to contact the patient”, and “Please specify other”. If the patient had a dose level reduction, concatenate the 
reduced dose level “Y: “.  
 
 
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Protocol 8400-401 
Listing 16.2.1.3 
 
End of Study (EOS) Visit Status 
 
Dose 
Group 
Patient 
Number 
Date of 
Visit/ Rel 
Day [1] 
Reason 
Visit Not 
Completed 
Date of 
Death/ 
Rel Day 
[1] 
Cause of 
Death 
Date Last 
Seen/ Rel 
Day [1]  
Completed 
24 Weeks 
of Study 
Treatment  
Primary Reason 
Patient did not 
Complete 24 Weeks 
Comments 
 
 
 
 
 
 
Death 
Lost to 
Follow-up 
Withdrawal 
of 
Consent 
Patient 
enrolled 
in 8400-
404 
 
 
 
 
Yes 
No 
Disease Progression 
AE related to study 
treatment 
AE not related to 
study treatment 
Pregnancy 
Lost to Follow-up 
Withdrawal of 
Consent  
Physician Decision 
Study terminated by 
Sponsor 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
 
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Listing 16.2.2.1 
 
Listing of Inclusion/Exclusion Criteria Not Met  
 
Dose 
Group 
Patient 
Number 
IN/EX Criteria Not Met 
Waiver 
Granted 
Waiver 
Details 
Comments 
 
 
 
Yes 
No 
 
 
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
 
 
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Listing 16.2.2.2 
 
Protocol Deviations 
 
Dose  
Group 
Patient  
Number 
Date of 
Deviation 
Rel 
Day 
[1] 
Category of Deviation 
Deviation Specifics 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion Criteria 
Not Met 
Prohibited Medication Taken 
Blood Specimen Collection 
Missed/ Out of Window 
Other Protocol Procedure 
Missed/ Out of Window 
IMO-8400 Dose Missed 
Other 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
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Protocol 8400-401 
Listing 16.2.3.1 
 
Study Populations 
 
Dose  
Group 
Patient  
Number 
Safety 
Population 
Efficacy 
Evaluable 
Population 
Reason Excluded from the 
Efficacy Evaluable Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
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Protocol 8400-401 
Listing 16.2.4.1 
 
Demographic Characteristics 
 
Dose Group 
Patient 
Number 
Informed 
Consent 
Date  
Protocol 
Version 
Date 
Date of 
Birth 
Age 
(Years) Sex 
Of Child-
bearing 
Potential 
Race 
Ethnicity 
 
 
 
 
 
 
 
 
 
 
 
 
Male 
Female 
Yes 
No 
American Indian or 
Alaska Native 
Asian 
Black 
Native Hawaiian or 
Other Pacific 
Islander 
White 
Other: 
Hispanic or 
Latino 
Not Hispanic 
or Latino 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: Concatenate specifics if “other” is chosen for race (Other: Specify).  
 
 
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Confidential 
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Protocol 8400-401 
Listing 16.2.4.2 
 
Medical History 
 
 
Dose Group 
Patient 
Number 
System 
Disease/ Procedure 
Start Date 
End Date 
Ongoing at 
Screening 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
No 
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
 
Programming note: if Ongoing = Yes, mark ONGOING in end date column.  
 
 
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Protocol 8400-401 
Listing 16.2.4.3 
 
Waldenström’s Macroglobulinemia Disease History 
 
 
 
 
 
 
 
Hospitalized in the Past 
Year 
 
Treatment-related AEs in Past 
3 Months 
Dose 
Group 
Patient 
Number 
Date of 
Diagnosis 
Date of 
First 
Treatment 
for WM 
Disease 
Status 
[1] 
IPSSWM 
[2] 
Y/N 
Date of 
Discharge 
Discharge 
Diagnosis 
 
Y/N 
Event 
Term 
Start 
Date 
End 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Refrac 
Relap 
Unk 
Low 
Inter 
High 
Yes 
No 
 
 
 
Yes 
No 
 
 
 
Note: AE = Adverse Event  
[1] Refrac = Refractory. Relap = Relapsed. Unk = Unknown.  
[2] IPSSWM = International Prognostic Scoring System for WM. Inter = Intermediate.  
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
  
 
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Protocol 8400-401 
Listing 16.2.4.4 
 
Prior Waldenström’s Macroglobulinemia Therapy 
 
Dose 
Group 
Patient 
Number 
Agent/ 
Treatment 
Other 
Treatment 
Agent/Treatment 
Categorized [1] 
Start 
Date 
Stop 
Date 
Best 
Clinical 
Response 
Reason for 
Discontinuation 
AEs 
experienced 
with this 
treatment 
Total 
Number of 
Prior 
Treatment 
Regimens 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: AE = Adverse Event. 
[1] Agent/Treatment categorized by clinical review.  
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If there was a combination of treatments recorded in eCRF and some of the drug names were categorized, please 
present it here as combination but with updated drug name. For example for pt 506-101 if ‘Ritux/Bendamustin’ was used, then 
‘Agent/Treatment’ column will state ‘Other’, ‘Other Treatment’ will state ‘Ritux/Bendamustin’ and Agent/Treatment Categorized’ will be 
‘Rituximab/Bendamustin’.  
 
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Protocol 8400-401 
Listing 16.2.4.5 
 
Baseline Waldenström’s Macroglobulinemia Symptoms 
 
Dose Group 
Patient 
Number 
Symptoms Present at 
Baseline 
Date of Occurrence Severity 
Clinically 
Significant 
 
 
Bleeding Events 
Fatigue 
Anemia 
Thrombocytopenia 
Leukemia / neutropenia 
Fever 
Hyperviscosity 
Neuropathy 
Lymphadenopathy 
Weight loss 
Headache 
Night Sweats 
Vision Changes 
Other:  
 
Grade 1: Mild 
Grade 2: Moderate 
Grade 3: Marked 
Grade 4: Extreme 
 
Yes 
No 
 
 
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: Concatenate specifics if “other” is chosen as a sign/symptom (Other: Specify).  
 
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Confidential 
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Protocol 8400-401 
Listing 16.2.4.6 
 
MyD88 L265P and CXCR4 Mutation Status 
 
Dose 
Group 
Patient Number 
Date of 
Assessment 
Rel Day [1] 
Mutation 
Mutation Status  
 
 
 
 
MyD88 L265P 
CXCR4 
Present 
Absent 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
 
 
 
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Protocol 8400-401 
Listing 16.2.5.1 
 
Study Drug Exposure 
 
Dose 
Group: 
[Descri
be]Pati
ent 
Number 
Cycle/
Week  
Both 
Doses 
Admin-
istered 
Inj-
ection 
Loca-
tion 
Date/ 
Time  
Rel 
Day 
[1]  
Site of 
Injec-
tion 
[2] 
 
Volume 
Dis-
pensed 
(mL) 
Dose 
(mg) 
[3] 
Entire 
Dose 
Admin-
istered 
Reason Dose 
Missed [4] 
Cum-
ulative 
Exposure 
(mg) [5] 
 
 
Yes 
No: 
Only 1 
No: 
Neither 
1 
2 
Site 
Home 
Visit 
 
 
 
 
 
Yes 
No: 
[Specify] 
AE-Rel 
AE-NR 
Missed Visit  
Other: 
[Specify] 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] RUQ= Right Upper Quadrant, LUQ= Left Upper Quadrant, RLQ= Right Lower Quadrant, LLQ= Left Lower Quadrant.  
[3] Calculated as [assigned dose (mg/kg) * volume administered (mL)] / concentration of 0.007 (mL/kg). 
[4] AE-Rel= Treatment-related AE. AE-NR = Nontreatment-related AE.  
[5] Cumulative exposure is the sum of all doses administered.  
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: if Site = “Other”, concatenate specifics, “Other Injection Site” 
Programming note: If entire dose not administered, concatenate specifics “Please explain why entire dose was not administered.” If the 
dose was missed and other was selected as the reason, concatenate specifics.  Reason Dose Missed is from the SAD raw dataset. 
 
 
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Listing 16.2.6.1 
 
Overall Disease Response 
 
Dose 
Group 
Patient 
Number 
Best 
Overall 
Response  
Date of First 
Occurrence of Best 
Overall Response/ 
Rel Day [1] 
Best IgM 
Response 
Type of Best 
IgM Response 
Date of Disease 
Progression/ 
Rel Day  
Date of 
Last 
Disease 
Assessment/ 
Rel Day 
 
 
 
CR 
VGPR 
PR 
MR 
SD 
PD 
NE 
 
CR 
VGPR 
PR 
MR 
SD 
PD 
NE 
Monoclonal 
Total 
 
 
 
 
 
 
 
 
Note: Disease Response assessed by the Investigator based on the VIth International Workshop on Waldenström’s Macroglobulinemia (Owen 
et al, 2012). CR = Complete response. VGPR = Very good partial response. PR = Partial response. MR = Minor response. SD = Stable 
disease. PD = Progressive disease. NE = Not evaluable.  
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
  
 
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Protocol 8400-401 
Listing 16.2.6.2 
 
Disease Response by Visit  
 
Dose 
Group 
Patient 
Number 
Visit 
Date of 
Assessment 
Rel 
Day 
[1] 
Parameter 
Clinical 
Response [2] 
Overall 
Response [3] 
Comments 
 
 
 
Serum Monoclonal IgM 
Bone Marrow 
Histology 
Adenopathy 
Organomegaly 
Cytopenias 
Symptoms 
Total IgM Response 
CR 
VGPR 
PR 
MR 
SD 
PD 
NE 
Delayed 
Response 
NA 
CR 
VGPR 
PR 
MR 
SD 
PD 
NE 
 
 
 
 
 
 
 
 
Note: Disease response assessed by the Investigator based on the VIth International Workshop on Waldenström’s Macroglobulinemia (Owen 
et al, 2012).  
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] CR = Complete response. VGPR = Very good partial response. PR = Partial response. MR = Minor response. SD = Stable disease. PD = 
Progressive disease. NE = Not evaluable. NA = Not applicable. * Indicates best IgM response 
[3] * Indicates best overall response  
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: Flag the first occurrence of the best overall response. There should be one overall response per visit, and it 
should only print once for that visit. 
 
 
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Protocol 8400-401 
Listing 16.2.6.3A 
 
Disease Assessment – Part 1: Lymphadenopathy and Hepatomegaly 
 
 
 
 
 
 
Physical assessment of lymphadenopathy 
 
Physical assessment of hepatomegaly 
Dose 
Group 
Patient 
Number 
Visit 
Date of 
Assessment 
Rel 
Day 
[1] 
Results 
Region 
Size 
(cm) 
Tenderness 
 
Results 
Abnormality 
Clinically 
Significant 
 
 
Normal  
Abnormal 
Not Done 
 
 
None 
Mild 
Moderate 
Severe 
 
Normal  
Abnormal 
Not Done 
 
Yes 
No 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
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Protocol 8400-401 
Listing 16.2.6.3B 
 
Disease Assessment – Part 2: Splenomegaly 
 
 
 
 
 
 
Physical assessment of splenomegaly 
Dose 
Group 
Patient 
Number 
Visit 
Date of 
Assessment 
Rel 
Day 
[1] 
Results 
Enlarged 
Palpable 
Tenderness 
 
 
Normal  
Abnormal 
Not Done 
Yes 
No 
Yes 
No 
None 
Mild 
Moderate 
Severe 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
 
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Protocol 8400-401 
Listing 16.2.6.4 
 
Immunoglobulin (IgM) Results 
 
 
 
 
 
 
Monoclonal IgM 
 
Total IgM  
Dose 
Group 
Patient 
Number 
Visit 
Date of 
Collection 
Rel 
Day 
[1] 
Result 
(g/dL) 
[2] 
Change 
from 
Baseline  
Percent 
Change 
from 
Baseline  
mIgM 
Disease 
Response 
[3] 
 
Result 
(mg/dL) 
[2] 
Change 
from 
Baseline  
Percent 
Change 
from 
Baseline  
IgM 
Disease 
Response 
[3] 
 
 
 
 
 
 
 
 
CR 
VGPR 
PR 
MR 
SD 
PD 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1.  
[2] * indicates Baseline value. Baseline = The most recent assessment before the first dose of study medication. 
[3] CR = Complete Response. VGPR = Very Good Partial Response. PR = Partial Response. MR = Minor Response. SD = Stable Disease. PD = 
Progressive Disease. # indicates best IgM response.   
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: IgM response taken from the database for the corresponding visit.  
 
 
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Protocol 8400-401 
Listing 16.2.6.5A 
 
Central Tumor Laboratory Assessments – Part 1: Electrophoresis and Protein Densitometry 
 
Dose Group: [Describe] 
 
 
 
 
 
By Electrophoresis 
 
Patient 
Number 
Visit 
Date/Time 
of 
Collection 
Rel 
Day 
[1] 
Albumin 
(unit) 
Alpha-1 
globulins 
(unit) 
Alpha-2 
globulins 
(unit) 
Beta 
globulins 
(unit) 
Gamma 
globulins 
(unit) 
M-spike 
(Monoclonal 
IgM)(unit)  
Total protein 
by 
densitometry 
(unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: L = Low, below normal range. H = High, above normal range. 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: Include normal range under the lab parameter and update units. Use tumor assessments category in ADLB. 
 
 
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Protocol 8400-401 
Listing 16.2.6.5B 
 
Central Tumor Laboratory Assessments – Part 2: Serum and Urine Assessments 
 
Dose Group: [Describe] 
 
 
 
 
 
Serum 
 
Urine 
Patient 
Number 
Visit 
Date/Time 
of 
Collection 
Rel 
Day 
[1] 
Protein 
Immuno-
fixation 
(unit) 
Serum 
Viscosity  
(unit) 
Lambda 
FLC 
(unit) 
Kappa 
FLC 
(unit) 
FLC 
Ratio 
Beta 2- 
micro-
globulin 
(unit) 
Total IgM 
(Immuno-
globulin) 
(unit) 
 
Lambda 
FLC 
(unit) 
Kappa 
FLC 
(unit) 
FLC 
Ratio  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: FLC = Free Light Chain. L = Low, below normal range. H = High, above normal range. 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: Include normal range under the lab parameter and update units. Use tumor assessments, serum free light chain, and 
urine free light chain categories in ADLB. 
 
 
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Protocol 8400-401 
Listing 16.2.6.6 
 
Local Tumor Laboratory Assessments  
 
Dose Group: [Describe] 
 
Patient 
Number 
Visit 
Date/Time of 
Collection 
Rel 
Day 
[1] 
M-spike 
(Monoclonal IgM) 
(unit)  
Total IgM 
(Immunoglobulin) 
(unit) 
 
 
 
 
 
 
 
 
 
 
 
Note: L = Low, below normal range. H = High, above normal range. * indicates result is clinically significant. 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: Use the out of range indicator from the local lab dataset (TLAL).  
 
 
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Protocol 8400-401 
Listing 16.2.6.7 
 
Central Efficacy Laboratory Assessments: Hemoglobin and Platelets 
 
Dose 
Group 
Patient 
Number 
Visit 
Date of 
Collection 
Rel 
Day 
[1] 
 
Hemoglobin 
(unit)  
Platelets 
(unit) 
Patient Has Been 
Transfused 
During the Study 
 
 
 
 
 
 
 
 
Yes 
No 
 
 
 
Note: L = Low, below normal range. H = High, above normal range. 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: Include normal range under the lab parameter, using central lab ranges. Use the normal range indicator in the local 
lab dataset for the local values. See SAP for identification of transufion status.  
 
 
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Protocol 8400-401 
Listing 16.2.6.8 
 
Central Efficacy Laboratory Assessments: Serum NF-ĸB 
 
Dose 
Group 
Patient 
Number 
Visit 
Date of 
Collection 
Rel 
Day 
[1] 
Time Point 
CD3+CD8+ 
CD3-
CD19+ 
CD3-
CD19+CD20+ 
CD3-
CD19+CD23-
CD10- 
Comments 
 
 
 
 
 
Pre Dose 
4 Hour Post 
Dose 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: Include normal range under the lab parameter if available. These data will be included in an external Excel 
spreadsheet.  
 
 
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Protocol 8400-401 
Listing 16.2.6.9 
 
Immunogenicity Results: Anti-IMO-8400 Antibodies 
 
Dose 
Group 
Patient 
Number 
Visit 
Collection 
Date  
Rel Day 
[1] 
Screening 
Result 
% Inhibition 
Confirmatory 
Result 
Titer 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: These data will be included in an external Excel spreadsheet.  
 
 
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Protocol 8400-401 
Listing 16.2.6.10A 
 
Serum Cytokines Test – Part 1 
 
Dose 
Group 
Patient Number 
Date of 
Collection 
Rel 
Day 
[1] 
FGF-
Basic   
(pg/mL)  
IL-
1beta 
(pg/mL) 
G-CSF 
(pg/mL)  
IL-10  
(pg/mL)  
IL-13 
(pg/mL)  
IL-6 
(pg/mL)  
IL-12 
(pg/mL)  
RANTES 
(pg/mL) 
Eotaxin 
(pg/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
Programming note: These data will be included in an external Excel spreadsheet. Include all cytokines. Create Parts 2 and 3, etc. as 
needed. Include normal range under the parameter if available. 
 
Repeat for:  
Listing 16.2.6.10B  Serum Cytokines Test – Part 2 
Listing 16.2.6.10C  Serum Cytokines Test – Part 3 
Listing 16.2.6.10D  Serum Cytokines Test – Part 4 
 
 
 
 
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Listing 16.2.6.11 
 
Bone Marrow Biopsy Results 
 
Dose  
Group 
Patient 
Number 
Type of 
Lab 
Visit 
Date Sample 
Collected 
Rel 
Day 
[1] 
% Lympho-
plasmacytic 
Lymphoma 
Cell 
Involvement 
Change 
from 
Baseline 
Biopsy 
Pathology 
Report 
Aspirate 
Flow 
Cytometry 
Report 
Biopsy 
Comment 
 
 
 
 
 
 
 
 
 
 
 
 
Central  
Local 
 
 
 
 
 
 
 
 
 
 
Note: Baseline = The most recent assessment before the first dose of study medication. 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX  
 
 
 
 
DATE: DDMMMYYYY HH:MM 
 
 
 
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Statistical Analysis Plan 
 
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Confidential 
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Protocol 8400-401 
Listing 16.2.7.1 
 
Adverse Events by Patient and MedDRA System Organ Class / Preferred Term 
 
Dose Group:  
 
 
 
Onset 
 
End 
 
 
 
 
Patient 
Number 
SOC 
[1] 
Preferred 
Term 
Date/ 
Time 
Rel 
Day 
[2] 
 
Date/ 
Time 
Rel 
Day 
[2] 
Sever-
ity 
[3] 
SAE 
TEAE 
DLT 
Rela-
tionship 
[4] 
Action 
Taken 
with IMO-
8400 
Action 
Taken for 
AE 
Sequelae 
at 
Resolution 
 
 
 
 
 
 
 
 
 
Yes 
No 
Yes 
No 
Yes 
No 
 
 
 
Yes 
No 
 
 
 
 
 
 
 
Note: SOC = System Organ Class. SAE = Serious adverse event. TEAE = Treatment-emergent adverse event. DLT = Dose limiting toxicity. CM 
= Concomitant medication. Adverse events coded per MedDRA version 16.1.  
[1] Refer to listing 16.0.1 for the full SOC name associated with the corresponding abbreviation.                                      
[2] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[3] 1 = Grade 1: Mild. 2 = Grade 2: Moderate. 3 = Grade 3: Marked. 4 = Grade 4: Extreme. 5 = Grade 5: Death. 
[4] Relationship to Study Drug: Prob Rel = Probably Related, Poss Rel = Possibly Related, Unlike Rel = Unlikely Related, Not Rel = Not 
related. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If sequelae at resolution, concatenate specifics (Yes: Specify sequelae). 
 
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Statistical Analysis Plan 
 
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Confidential 
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Protocol 8400-401 
Listing 16.2.7.2 
 
Adverse Events by MedDRA System Organ Class and Preferred Term 
 
System Organ Class:  
 
 
 
Onset 
 
End 
 
 
 
 
Preferred 
Term  
Dose 
Group 
Patien
t 
Number 
Date/ 
Time 
Rel 
Day 
[1] 
 
Date/ 
Time 
Rel 
Day 
[1] 
Sever-
ity [2] SAE 
TEAE 
DL
T 
Rela-
tionship 
[3] 
Action 
Taken 
with IMO-
8400 
Action 
Taken 
for AE 
Sequelae 
at 
Resolutio
n 
 
 
 
 
 
 
 
 
 
Yes 
No 
Yes 
No 
Ye
s 
No 
 
 
 
Yes 
No 
 
 
 
 
 
 
 
Note: SAE = Serious adverse event. TEAE = Treatment-emergent adverse event. DLT = Dose limiting toxicity. CM = Concomitant medication. 
Adverse events coded per MedDRA version 16.1.  
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] 1 = Grade 1: Mild. 2 = Grade 2: Moderate. 3 = Grade 3: Marked. 4 = Grade 4: Extreme. 5 = Grade 5: Death. 
[3] Relationship to Study Drug: Prob Rel = Probably Related, Poss Rel = Possibly Related, Unlike Rel = Unlikely Related, Not Rel = Not 
related. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If sequelae at resolution, concatenate specifics (Yes: Specify sequelae). 
 
 
 
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Idera Pharmaceuticals, Inc. 
Confidential 
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Protocol 8400-401 
Listing 16.2.7.3 
 
Glossary of Adverse Event Verbatim Terms by MedDRA System Organ Class, Preferred Term, and Patient 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SOC = System Organ Class. Adverse events coded per MedDRA version 16.1. 
[1] Refer to listing 16.0.1 for the full SOC name associated with the corresponding abbreviation.                                       
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: Sort the listing by SOC, PT, Verbatim, Dose Group, and Patient Number. 
  
 
MedDRA 
 
 
 
SOC [1] 
Preferred Term 
Dose Group 
Patient Number 
Investigator Reported Term 
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Statistical Analysis Plan 
 
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Confidential 
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Protocol 8400-401 
Listing 16.2.7.4 
 
Injection Site Reaction Assessments  
 
 
 
 
 
 
 
 
 
 
Dose 
Group 
Patient 
Number 
Visit of 
Assessment 
Date of 
Assessment 
Rel 
Day 
[1] 
Time of 
Assessment  
Visit of 
Injection 
Site of 
Injection 
Any ISR 
Reported  
Previous ISR 
for Same Site 
 
 
 
 
 
 
 
 
Yes 
No 
Yes 
No 
 
 
 
 
 
 
 
 
 
 
 
Note: ISR = injection site reaction. If there was no injection site reaction noted, then further data was not recorded. 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
 
 
 
 
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Statistical Analysis Plan 
 
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Protocol 8400-401 
Listing 16.2.7.5 
 
Patient Reported Injection Site Reactions  
 
Dose 
Group 
Patient 
Number 
Date of 
Assessment/ 
Rel Day [1] 
Trait 
Date of 
Onset/ Rel 
Day [1] 
Date of 
Resolution/ 
Rel Day [1] 
Severity 
Reaction 
ongoing at 
time of 
assessment 
Sequelae 
ISR 
Treated 
 
 
 
 
 
 
 
Yes 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: ISR = injection site reaction.  
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If ISR treated, concatenate specifics for con med or other treatment.  
 
 
251-289


Statistical Analysis Plan 
 
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Confidential 
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Protocol 8400-401 
Listing 16.2.7.6 
 
Investigator Observed Injection Site Reactions  
 
Dose 
Group 
Patient 
Number 
Date of 
Assessment 
Rel 
Day 
[1] 
Date of 
Injection 
Visit of 
Injection 
Trait 
Status 
Severity 
Size 
(cm) 
ISR Treated 
 
 
 
 
 
 
Erythema 
Induration 
Tenderness 
Pain 
Pruritus 
Blister 
Ulceration 
Necrosis 
Present 
Absent 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
NA 
 
 
 
 
 
 
 
 
Note: NA = Not applicable. ISR = Injection site reaction. 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If ISR treated, concatenate specifics for con med or other treatment.  
 
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Statistical Analysis Plan 
 
Page 111 of 124 
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Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Listing 16.2.8.1A 
 
Central Laboratory Results: Hematology – Part 1 
Dose Group: [Description] 
 
Patient 
Number 
Visit 
Date/Time 
of 
Collection 
Rel 
Day 
[1] 
WBC 
Count 
(unit) 
RBC 
Count 
(unit) 
Hemo-
globin 
(unit)  
Hemato-
crit 
(unit) 
Platelet 
Count 
(unit) 
MCH 
(unit) 
MCHC 
(unit) 
MCV 
(unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: RBCs = Red Blood Cells, MCH = Mean Corpuscular Hemoglobin, MCHC = Mean Corpuscular Hemoglobin Concentration,  
MCV = Mean Corpuscular Volume, WBC = White Blood Cells. 
L = Low, below normal range. H = High, above normal range.  
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note: In all tables include normal range under the lab parameter. 
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Statistical Analysis Plan 
 
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Confidential 
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Protocol 8400-401 
Listing 16.2.8.1B 
 
Central Laboratory Results: Hematology – Part 2 
 
Dose Group: [Description] 
 
Patient 
Number 
Visit 
Date/Time of 
Collection 
Rel 
Day 
[1] 
Neutro- 
phils 
(unit) 
Eosino- 
phils 
(unit) 
Baso- 
phils 
(unit) 
Lympho- 
cytes 
(unit) 
Mono- 
cytes 
(unit) 
RDW 
(unit) 
Mean 
Platelet 
Volume 
(unit) 
Platelet 
Estimate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
Note: L = Low, below normal range. H = High, above normal range. RDW = Red Cell Distribution Width. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming Note:  
- 
Present in multiple listings as needed to present all parameters. In all central listings include normal range under the lab 
parameter. In local listings, there will not be a range, but use the range indicator from EDC for H or L flags. Include 
clinical significance if available. May need to present unit in the column (vs header), unless all observations are in the same 
unit for a parameter.  
- 
For serum complement, do not include Albumin: Globulin Ratio, but add in additional parameters (C3, CH50).  
- 
For urinalyais, add additional central urinalysis parameters to Part 5. Include RBC and WBC in Part 1. Local will have less 
parameters.  
  
 
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Statistical Analysis Plan 
 
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Confidential and Proprietary 
Repeat Listing 16.2.8.1B for: 
Listing 16.2.8.1C  Local Laboratory Results: Hematology – Part 1 
Listing 16.2.8.1D  Local Laboratory Results: Hematology – Part 2 
Listing 16.2.8.2A  Central Laboratory Results: Chemistry – Part 1 
Listing 16.2.8.2B  Central Laboratory Results: Chemistry – Part 2 
Listing 16.2.8.2C  Central Laboratory Results: Chemistry – Part 3 
Listing 16.2.8.2D  Local Laboratory Results: Chemistry – Part 1 
Listing 16.2.8.2E  Local Laboratory Results: Chemistry – Part 2 
Listing 16.2.8.2F  Local Laboratory Results: Chemistry – Part 3 
Listing 16.2.8.3A  Central Laboratory Results: Urinalysis – Part 1 
Listing 16.2.8.3B  Central Laboratory Results: Urinalysis – Part 2 
Listing 16.2.8.3C  Central Laboratory Results: Urinalysis – Part 3 
Listing 16.2.8.3D  Central Laboratory Results: Urinalysis – Part 4 
Listing 16.2.8.3E  Central Laboratory Results: Urinalysis – Part 5  
Listing 16.2.8.3F  Local Laboratory Results: Urinalysis – Part 1 
Listing 16.2.8.3G  Local Laboratory Results: Urinalysis – Part 2 
Listing 16.2.8.3H  Local Laboratory Results: Urinalysis – Part 3 
Listing 16.2.8.4A  Central Laboratory Results: Coagulation 
Listing 16.2.8.4B  Local Laboratory Results: Coagulation 
Listing 16.2.8.5A  Central Laboratory Results: Serum Complement  
Listing 16.2.8.5B  Local Laboratory Results: Serum Complement  
Listing 16.2.8.6  Local Laboratory Results: Cryoglobulins 
Listing 16.2.8.7  Local Laboratory Results: Cold Agglutinins 
 
 
 
 
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Statistical Analysis Plan 
 
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Idera Pharmaceuticals, Inc. 
Confidential 
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Protocol 8400-401 
Listing 16.2.8.8 
 
Laboratory Results: Serology 
 
Dose  
Group 
Patient Number 
Visit 
Date/Time of 
Collection 
Rel 
Day 
[1] 
Lab Type 
HBsAg 
HIV 
HCV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local  
Central 
 
 
 
Note: HBsAg = Hepatitis B surface antigen, HIV = Human immuno deficiency virus, HCV = Hepatitis C virus. 
 [1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: if there are local and central results, include the lab type column.  
 
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Statistical Analysis Plan 
 
Page 115 of 124 
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Idera Pharmaceuticals, Inc. 
Confidential 
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Protocol 8400-401 
Listing 16.2.8.9 
 
Pregnancy Test Results 
 
Dose 
Group 
Patient Number 
Age 
Visit 
Date/Time 
Sample 
Collected 
Rel Day [1] 
Lab Type 
Test Type 
Result of 
Pregnancy Test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local  
Central 
Urine 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
  
 
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Statistical Analysis Plan 
 
Page 116 of 124 
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Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Listing 16.2.9.1 
 
Vital Signs 
 
Dose 
Group 
Patient 
Number 
 
Date of 
Assessment 
Rel 
Day 
[1] 
 
Time 
Point 
Height 
(cm) 
Weight 
(kg) 
SBP 
(mmHg) 
DBP 
(mmHg) 
Heart Rate 
(beats/min) 
Respiratory 
Rate 
(beats/min) 
Temperature 
(oC) 
Any 
Abnormal, 
CS Results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SBP = Systolic Blood Pressure. DBP = Diastolic Blood Pressure. CS = Clinically Significant.  
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
  
 
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Statistical Analysis Plan 
 
Page 117 of 124 
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Confidential 
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Protocol 8400-401 
Listing 16.2.9.2 
 
Physical Examination Findings 
 
Dose 
Group 
Patient 
Number 
Date of 
Assessment 
Rel Day 
[1] 
 
Time 
Point 
Body System 
Findings 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
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Statistical Analysis Plan 
 
Page 118 of 124 
Protocol 8400-401, Final Version 2.0 
21 April 2017 
 
 
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Confidential and Proprietary 
Idera Pharmaceuticals, Inc. 
Confidential 
Page x of y 
Protocol 8400-401 
Listing 16.2.9.3 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
Dose 
Group 
Patient Number Visit 
Date of 
Assessment 
Rel Day 
[1] 
ECOG Score [2] 
 
 
 
 
 
 
 
 
 
 
 
  
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] 0 = Fully active, able to carry on all pre-disease performance without restriction. 1 = Restricted in physically strenuous 
activity but ambulatory and able to carry out work of a light or sedentary nature. 2 = Ambulatory and capable of all self-care but 
unable to carry out any work activities; up and about more than 50% of waking hours. 3 = Capable of only limited self-care; 
confined to bed or chair more than 50% of waking hours. 4 = Completely disabled. 5 = Dead.  
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: HH:MM/DDMMMYYYY 
  
 
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Statistical Analysis Plan 
 
Page 119 of 124 
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Protocol 8400-401 
Listing 16.2.9.4 
 
12-Lead Electrocardiogram Interval and Overall Assessment 
 
 
 
 
 
 
 
Intervals (msec) 
 
 
Dose 
Group 
Patient 
Number 
Date/Time 
of 
Assessment 
Rel 
Day 
[1] 
Time 
Point 
Vent-
ricular 
Rate 
(bpm) 
RR  PR  
QRS 
QT 
QTc 
Method 
QTcF 
[2] 
ECG 
Result 
[3] 
Comment 
 
 
 
 
 
 
 
 
 
 
 
QTcB 
QTcF 
 
Normal 
Ab-NCS 
Ab-CS 
 
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1.  
[2] If QT interval available, then QTc-Fridericia calculated. If not, then QTc Interval and Method taken from ECG Strip. QTcF is 
calculated using the formula QT/(RR^(1/3))                                              
[3] ECG Result: Ab-NCS = Abnormal, Not Clinically Significant; Ab-CS = Abnormal, Clinically Significant.                                
 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
  
 
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Statistical Analysis Plan 
 
Page 120 of 124 
Protocol 8400-401, Final Version 2.0 
21 April 2017 
 
 
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Idera Pharmaceuticals, Inc. 
Confidential 
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Protocol 8400-401 
Listing 16.2.9.5 
 
Concomitant Medications 
 
Dose Group 
Patient Number 
Medication 
ATC Class / 
Preferred 
Name 
Start Date/ 
Rel Day [1] 
End Date/ 
Rel Day [1] 
Dose 
Unit 
Route 
Frequency 
[2] 
Used 
to 
treat 
an AE 
AE 
# 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: ATC = Anatomic Therapeutic Classification from WHO Drug Dictionary Q12013. AE = Adverse Event.   
[1] Rel Day = Calendar Days from the first dose of IMO-8400, designated day 1. 
[2] BID = Twice a day, TID = Three times a day, QID = Four times a day, QD = Once a day, QOD = Every other day, QWK = Every week,    
      Q2WK = Once every 2 weeks, Q3WK = Once every 3 weeks, QH = Every hour, Q4H = Every 4 hours, Q6H = Every 6 hours,    
      OTO = One time only, PRN = As needed. 
 
PROGRAM NAME: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DATE: DDMMMYYYY HH:MM 
 
Programming note: If medication is ongoing, enter ONGOING in end date column. If other is selected for unit, route, or frequency, 
concatenate specifics (Other: Specify). Update drug dictionary version if applicable.  
  
 
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9. 
REVISION HISTORY 
9.1. 
Statistical Analysis Plan Version 2.0:  21 April 2017 
Rationale of Revisions 
Changes were made to the SAP to correspond with Protocol Version 7.0 dated 14 March 2016, 
including updates in study procedures and additional dose escalation cohorts. Changes 
throughout the document include minor editorial changes.  
Description of Revisions Affecting Section 2 
- 
Section 2.2.5 Safety, Efficacy, and Pharmacokinetic Parameters: Efficacy parameters 
were updated to include the parameters described in Protocol Section 12.4.1.2. Details of 
the PK parameters were removed, as they will be described in a separate report. 
Description of Revisions Affecting Section 3 
- 
Section 3.1 Population Definitions: Additional detail was added to the EE Population 
definition. The Safety/ITT Population was renamed to the Safety Population. The PK 
and PP Populations were removed.  
Description of Revisions Affecting Section 4 
- 
Section 4.2 General Methods: The relative day logic was updated to remove the flagging 
of the last day of treatment with an ‘L’ and post-treatment days with a ‘P.’ Detail was 
added for handling of missing data.  
Description of Revisions Affecting Section 5:  
- 
Section 5.2 Demographics and Baseline Characteristics: Disease history was updated to 
include detail of parameters included, and derivation details for IPSSWM.  
- 
Section 5.3.1 Study Drug Exposure: Details were added to this section to include full 
calculations for deriving dose from the information collected on the eCRF.  
- 
Section 5.3.2 Adverse Events: Details were added to clarify summaries are on TEAEs 
only. A summary of SAEs was added.  
- 
Section 5.3.3 Laboratory Data: Details were added regarding local and central laboratory 
results. The listing of abnormal laboratory values was removed.  
- 
Section 5.3.4 Vital Signs: The box plot presenting vital sign values over time was 
removed.  
- 
Section 5.3.6 Electrocardiogram: Added additional tabulations of ECG data, including 
shift tables for QTcF and heart rate.  
- 
Section 5.4 Efficacy Analysis:  
The following efficacy analyses were added:  
o Summary of monoclonal IgM 
o Summary of best observed response by CXCR4 mutation status 
o Summary of hematology and platelet count values 
The following efficacy analyses were removed:  
o Duration of objective response 
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o Time to progression 
o Progression-free survival 
o Time to best observed response 
o Repeated measures mixed model for the change in quantitative serum levels of 
total IgM 
o ORR and time to progression exploratory analysis by mutation status 
o Figures for cytokine laboratory values 
- 
Section 5.5 Pharmacokinetic Analysis: Details of the PK analysis were removed, as it 
will be described in a separate report. 
 
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10.
APPENDICES
10.1. 
Appendix 1: Classification of Disease Response for Waldenström’s
Macroglobulinemia
Table 10.1 presents disease response categories used in this study, and is reproduced from the 
reference Owen et al 2008 and Protocol Section 16.2.  
Table 10.1  
Categorical Response Definitions 
Response 
Category 
Definition 
Complete 
response (CR) 
Absence of serum monoclonal IgM protein my immunofixation 
Normal serum IgM level 
Complete resolution of extramedullary disease, i.e., lymphadenopathy 
and splenomegaly if present at baseline 
Morphologically normal bone marrow aspirate and trephine biopsy 
Very good 
partial response 
(VGPR) 
Monoclonal IgM protein is detectable 
≥ 90% reduction in serum IgM level from baseline* 
Complete resolution of extramedullary disease, i.e., lymphadenopathy/ 
splenomegaly if present at baseline 
No new signs or symptoms of active disease 
Partial response 
(PR) 
Monoclonal IgM protein is detectable 
≥ 50% but < 90% reduction in serum IgM level from baseline* 
Reduction in extramedullary disease, i.e., lymphadenopathy/ 
splenomegaly if present at baseline 
No new signs or symptoms of active disease 
Minor response 
(MR) 
Monoclonal IgM protein is detectable 
≥ 25% but < 50% reduction in serum IgM level from baseline* 
No new signs or symptoms of active disease 
Stable disease 
(SD) 
Monoclonal IgM protein is detectable 
< 25% reduction and < 25% increase in serum IgM level from baseline* 
No progression in extramedullary disease, i.e., lymphadenopathy/ 
splenomegaly  
No new signs or symptoms of active disease 
Progressive 
disease (PD) 
≥ 25% increase in serum IgM level* from lowest nadir (requires 
confirmation) and/or progression in clinical features attributable to the 
disease 
* Sequential changes in IgM levels may be determined either by M protein quantitation by
densitometry or total serum IgM quantitation by nephelometry 
The Third International Workshop for WM also defined the following categories: 
•
Not evaluable response: Reserved for situations in which there is insufficient data for a
determination of response to treatment.
•
Delayed response: A delayed response is described particularly after treatment with
purine analogue or monoclonal antibody. The recommendation was that patients should
be followed for at least 2 weeks after treatment initiation to be considered unresponsive
to therapy.
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10.2. 
Appendix 2: IMO-8400 Subcutaneous Injection Site Grading (Local 
Reactions) 
Finding 
Mild 
Moderate 
Severe 
Pain 
Present; no 
limitations in ADL 
Limitations in age-appropriate 
instrumental ADL or requires 
repeated non-narcotic pain 
reliever  
Limitations in self-care 
ADL or interferes with 
sleep, or requires 
repeated narcotic pain 
reliever  
Tenderness 
Mild discomfort 
with pressure  
Discomfort with touch  
Discomfort elicited by 
clothing or bedsheets  
Pruritus 
(itch) 
Present, but 
minimally 
distracting  
Present, distracting during 
routine activities  
Interferes with sleep  
Induration 
(swelling, 
edema) 
Present; no 
limitations in ADL  
Limitations in age-appropriate 
instrumental ADL  
or requires repeated treatment 
(excluding systemic steroids).  
Limitations in self-care 
ADL or requires 
treatment with systemic 
steroids  
Pain: discomfort or unpleasant feeling (e.g., headache) experienced while at rest or with activity; in 
addition to location, the patient’s description may include intensity as well a distinctive quality (e.g., 
burning, stabbing). 
Tenderness: discomfort elicited when the area is touched either intentionally or accidently. 
Pruritus (itch): an unpleasant sensation that evokes the desire or reflex to scratch. (In contrast, pain and 
tenderness evoke a reflex to withdraw.) 
Activities of daily living (ADL) are classified into two subsets: 
– Instrumental ADL, e.g., preparing meals, shopping for groceries or clothes, using the telephone, 
managing money; 
– Self-care ADL, e.g., bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not being bedridden. 
 
10.3. 
Appendix 3: Intensity of AE of Injection Site Reaction 
Finding 
Mild 
Moderate 
Severe 
Tenderness with 
or without 
associated 
symptoms  
(e.g., warmth, 
erythema, 
itching)  
Pain; 
lipodystrophy; 
edema; phlebitis  
Ulceration or necrosis;  
severe tissue damage;  
operative intervention 
indicated  
Life-threatening 
consequences;  
urgent intervention 
indicated  
Note: Table is based on NCI-CTCAE v.4.03. Definition of Injection Site Reaction: A disorder 
characterized by an intense adverse reaction (usually immunologic) developing at the site of an injection.  
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Pharmacokinetic Statistical Analysis Plan (PK SAP) 
 
Protocol Title: 
8400-401: Phase 1/2 Open-label, Multiple-dose, Dose-
escalation Study to Evaluate the Safety and Tolerability of 
IMO-8400 in Patients with Relapsed or Refractory 
Waldenström’s Macroglobulinemia 
 
8400-402: Phase 1/2 Open-label, Multiple-dose, Dose-
escalation Study to Evaluate the Safety and Tolerability of 
IMO-8400 in Patients with Relapsed or Refractory 
Diffuse Large B-cell Lymphoma and Presence of the 
MYD88 L265P Mutation 
Investigational Drug: 
IMO-8400 
Protocol Number: 
8400-401, 8400-402 
IND Number: 
119651 
Sponsor: 
 
Prepared By:  
Idera Pharmaceuticals, Inc. 
167 Sidney Street, 
Cambridge, MA 02139, USA 
 
KinderPharm LLC 
100 Arrandale Blvd. (Suite 101)  
Exton, PA 19341 
 
Original Protocol Date: 
 
 Protocol Amendment Date: 
 
8400-401: 11 Oct. 2013, 8400-402: 7 March, 2014 
 
8400-401: 18 Nov. 2013, 23 July 2014, 22 Sept. 2014, 25 
Feb. 2015, 13 Aug. 2015, 14 March 2016  
8400-402: 7 Nov. 2014, 12 Nov. 2014, 9 June 2015, 29 
Jan. 2015  
 
SAP Date: 
24 March 2017 
SAP Version Number: 
1.0 
SAP Status 
Draft-1 
 
 
 
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HISTORY LOG FOR REVISIONS MADE AFTER THE INITIAL APPROVAL 
Revision 
Date** 
Author 
of 
Revision* 
Section(s) 
Modified 
Description and/or Reason(s) Revision 
 
 
 
 
 
 
 
 
 
 
 
 
* Provide first initial and last name. 
** Update the last revision dates on the cover page and the footer. 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................... 7 
1 
INTRODUCTION ................................................................................................................... 8 
1.1 
Objective of the PK Statistical Analysis Plan .................................................................. 8 
2 
STUDY OBJECTIVES ........................................................................................................... 8 
2.1 
Study 8400-401 ................................................................................................................ 8 
2.1.1 
Primary Objective ..................................................................................................... 8 
2.1.2 
Secondary Objective ................................................................................................. 8 
2.1.3 
Exploratory Objectives ............................................................................................. 9 
2.2 
Study 8400-402 ................................................................................................................ 9 
2.2.1 
Primary Objective ..................................................................................................... 9 
2.2.2 
Secondary Objectives................................................................................................ 9 
2.2.3 
Exploratory Objectives ............................................................................................. 9 
3 
STUDY DESIGN .................................................................................................................... 9 
3.1 
8400-401........................................................................................................................... 9 
3.1.1 
Study Overview ........................................................................................................ 9 
3.2 
8400-402......................................................................................................................... 11 
3.2.1 
Study Overview ...................................................................................................... 11 
4 
PHARMACOKINETIC ANALYSIS .................................................................................... 13 
4.1 
PK Population ................................................................................................................ 13 
4.2 
Blood Sampling Schedule .............................................................................................. 13 
4.2.1 
8400-401 ................................................................................................................. 13 
4.2.2 
8400-402 ................................................................................................................. 13 
4.3 
Pharmacokinetic Parameters .......................................................................................... 13 
4.3.1 
8400-401 ................................................................................................................. 13 
4.3.2 
8400-402 ................................................................................................................. 14 
4.4 
Handling of Missing Sampling or Concentration Data .................................................. 14 
4.5 
Handling of Concentration Values below the Limit of Quantification (BLQ) .............. 15 
4.6 
Handling of Outliers ....................................................................................................... 15 
4.7 
Handling of Actual vs. Planned Sampling Timepoints .................................................. 15 
4.8 
Handling of Individual Data and Summary Data Formats ............................................. 15 
5 
STATISTICAL METHODS.................................................................................................. 15 
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5.1 
General Statistical Considerations ................................................................................. 15 
5.2 
Statistical Assessment .................................................................................................... 16 
6 
PRESENTATION OF RESULTS ......................................................................................... 16 
6.1 
Listings ........................................................................................................................... 16 
6.2 
Tables ............................................................................................................................. 16 
6.3 
Figures ............................................................................................................................ 17 
 
  
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
AUC0-t 
Area Under the Concentration-Time Curve from time 0 to the last time point 
with a concentration level ≥ LOQ 
BLQ 
Below the Lower Limit of Quantitation 
CFR 
Code of Federal Regulation 
CI 
Confidence Interval 
Cmax 
Maximum Observed Concentration 
CV 
Coefficient of Variation 
D 
Dose 
DLT 
Dose-Limiting Toxicities 
EOT 
End-of-Treatment 
EOS 
End-of-Study 
h 
Hour 
LLOQ 
Lower Limit of Quantification 
LOQ 
Limit of Quantitation 
Max 
Maximum Value 
Min 
Minimum Value 
MTD 
Maximum Tolerated Dose 
NCA 
Non-Compartmental Analysis 
PK 
Pharmacokinetic(s) 
PKS 
Pharsight Knowledgebase Server  
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
TLFs 
Tables, Listings and Figures 
Tmax 
Time to reach Maximum Concentration 
ULOQ 
Upper Limit of Quantification 
 
 
 
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1 
INTRODUCTION 
1.1 
Objective of the PK Statistical Analysis Plan 
This statistical analysis plan (SAP) describes the planned analysis of the pharmacokinetic (PK) 
data from two Phase 1/2 studies (8400-401 and 8400-402). A detailed description of the tables, 
listings and figures (TLFs) to be presented in the stand-alone PK report for each study is provided 
in the accompanying TLFs shell document. 
The intent of this document is to provide guidance for the analysis of the pharmacokinetic data 
collected as part of protocols 8400-401 and 8400-402. In general, the analyses come directly from 
the protocols, unless they have been modified by agreement by Idera Pharmaceuticals, Inc. A 
limited amount of information concerning these two studies (e.g. objectives, study design) are 
summarized to help the reader interpret the accompanying TLFs shell. This information is not a 
synopsis of the study; it is simply extracted from the protocol to guide the statistical analysis of 
the PK data. Attached signatures indicate approval of the PK SAP, as well as the accompanying 
TLFs shell. This PK SAP must be approved prior to database lock. When the PK SAP and TLFs 
shell are agreed upon and finalized, they will serve as the template for PK portion of the clinical 
study reports (CSR). 
This SAP supersedes the statistical considerations identified in the protocol; where considerations 
are substantially different, they will be identified. If additional analyses are required to supplement 
the planned analyses described in this SAP they may be performed and will be identified in the 
appropriate section of the PK report. Any substantial deviations from this SAP will be approved 
by Idera Pharmaceuticals, Inc. Deviations from this SAP will be documented in the PK report. 
2 
STUDY OBJECTIVES 
2.1 
Study 8400-401 
2.1.1 
Primary Objective 
To evaluate the safety and tolerability of escalating dose levels of IMO-8400 administered by 
subcutaneous (SC) injection in patients with relapsed or refractory Waldenström’s 
Macroglobulinemia (WM). 
 
2.1.2 
Secondary Objective 
• To assess the treatment effect (clinical activity) of escalating dose levels of IMO-8400 using 
disease-specific international guidelines for classifying clinical response. 
• To identify an optimal dose of IMO-8400 for further clinical evaluation. 
• To characterize the pharmacokinetics (PK) of escalating dose levels of IMO-8400 
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administered by SC injection. 
 
2.1.3 
Exploratory Objectives 
• To investigate associations between the treatment effect of IMO-8400 and selected biomarkers 
(e.g., serum cytokines). 
• To correlate the presence of myeloid differentiation primary response gene 88 (MYD88) L265P 
mutation with clinical outcome. 
• To assess the potential immunogenicity of IMO-8400 administered by SC injection. 
2.2 
Study 8400-402 
2.2.1 
Primary Objective 
• To evaluate the safety and tolerability of escalating dose levels of IMO-8400 administered by 
subcutaneous (SC) injection in patients with relapsed or refractory non-GCB subtype diffuse 
large B-cell lymphoma (DLBCL). 
 
2.2.2 
Secondary Objectives 
• To assess the treatment effect (clinical activity) in patients with non-GCB subtype DLBCL with 
MYD88 L265P mutations using disease-specific international guidelines for classifying clinical 
response. 
• To identify an optimal dose of IMO-8400 for further clinical evaluation in B-cell malignancies. 
• To characterize the pharmacokinetics of escalating dose levels of IMO-8400 administered by SC 
injection. 
 
2.2.3 
Exploratory Objectives 
• To investigate associations between the treatment effect of IMO-8400 and selected biomarkers 
(e.g., serum cytokines). 
To assess the potential immunogenicity of IMO-8400 administered by SC injection. 
3 
STUDY DESIGN 
3.1 
8400-401 
3.1.1 
Study Overview 
This was an open-label, multiple-dose, dose escalation study of IMO-8400 in patients with 
relapsed or refractory WM. The dose-escalation cohorts (3 to 6 patients each) were systematically 
evaluate the safety and tolerability of IMO-8400 at increasing dose levels in order to identify the 
maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D). The planned dose escalation 
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cohort levels for IMO-8400 were 0.6, 1.2, 2.4, and 3.6 mg/kg administered once weekly and 1.2 
mg/kg administered twice weekly (Table 1). All dose levels (0.6 to 3.6 mg/kg/week) as SC 
injections were normalized by body weight at screening and advised to be recalculated if change 
in body weight from screening exceeds 10% (±).  
 
Each dose-escalation cohort is expected to enroll at least 3 patients, with a maximum of 6. The 
criteria include: If all of the initial 3 patients complete 4 weeks of treatment without a DLT event, 
the DRC will conduct a dose-escalation review. If 1 of the initial 3 patients at any of these dose 
levels experience a DLT event prior to completing 4 weeks of treatment, then enrollment at that 
dose level will continue to a total of 6 patients and the dose-escalation review will be done when 
all 6 patients have completed 4 weeks of treatment. If 2 patients at any of these dose levels 
experience DLT events during the first 4 weeks of treatment, then no further patients will be 
enrolled until the DRC completes a review, which should be done as soon as feasible. All doses 
were administered by SC injection. For Dose Level 3 (refer to Table 1), the total dose was divided 
into 2 equal portions (1.2 mg/kg twice weekly), administered as separate SC injections over the 
course of the week, approximately 72 to 96 hours apart (minimum 48 hours). After establishing 
the safety for the 2.4 mg/kg/week as a divided weekly dose (1.2 mg/kg twice weekly), the same 
dose level of 2.4 mg/kg/week and subsequent dose levels were given as a once weekly 
administration.  
 
The expansion cohorts provide for additional enrollment at agreed upon dose levels to assess the 
dose dependence of clinical response. Once the MTD or a potential RP2D and/or schedule have 
been established during dose escalation, up to 22 patients will be treated at the RP2D level 
according to this schedule. The Sponsor may decide at any point during the expansion phase to 
modify the RP2D based on emerging data including, but not limited to, safety, DLTs, PK, and 
clinical activity. If such a change is made, enrollment may continue at the selected dose level in 
up to 22 patients. Also, patients being treated with lower dose levels may have their doses escalated 
to the RP2D/MTD, after discussion and agreement between the Sponsor and the Investigator. 
 
Screening will be done within 21 days prior to Day 1 (the first injection of study drug). Treatment 
is scheduled to be administered in 8-week cycles until progressive disease, unacceptable toxicity, 
withdrawal of consent, or end of study. Assessments for treatment response (or disease 
progression) are scheduled every 8 weeks ± 1 week (at the start of a new cycle) for clinical 
assessments, and every 4 weeks ± 1 week for laboratory assessments. End-of-Treatment (EOT) 
visit will be performed within 5 days of the decision to terminate treatment. End-of-Study (EOS) 
visit will be performed 30 to 35 days after the last dose of study drug. 
 
 
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Table 1: Study Design for 8400-401 
Dose Level 
IMO-8400 Dose (mg/kg) 
Frequency 
Initial Cohort Size 
1  
(starting dose) 
0.6 
Once Weekly 
3 to 6 
2 
1.2 
Once Weekly 
3 to 6 
3 
1.2 
Twice Weekly 
3 to 6 
4 
2.4 
Once Weekly 
3 to 6 
5 
3.6 
Once Weekly 
3 to 6 
 
3.2 
8400-402 
3.2.1 
Study Overview 
This is an open-label, multiple-dose, dose escalation study of IMO-8400 in patients with relapsed 
or refractory DLBCL of non-GCB subtype. The study is a Phase 1/2 study in which Phase 1 will 
consist of a dose escalation to determine the RP2D.  
 
The dose escalation cohorts will permit systematic evaluation of the safety and tolerability of IMO-
8400 at increasing dose levels in order to identify the MTD. The planned dose escalation cohort 
levels for IMO-8400 are 0.3, 0.6, and 1.2 mg/kg administered twice weekly and 2.4 and 3.6 mg/kg 
administered once weekly (Table 2). Additional dose levels, schedules, and routes of 
administration may be evaluated based upon the emerging data. Dosing is normalized to body 
weight, and all doses will be administered by SC injection. The Investigators and Sponsor will 
review available toxicity information (including adverse events [AEs] that are not DLTs), PK and 
clinical activity data to determine the MTD.  
 
Table 2: Study Design for 8400-402 
Dose Level 
IMO-8400 Dose (mg/kg) 
Frequency 
Initial Cohort Size 
1  
(starting dose) 
0.3 
 
Twice Weekly 
 
3 to 6 
 
2 
0.6 
Twice Weekly 
3 to 6 
3 
1.2 
Twice Weekly 
3 to 6 
4 
2.4 
Weekly 
3 to 6 
5 
3.6 
Weekly 
3 to 6 
 
 
Once the RP2D has been established, additional patients will be treated in a dose expansion 
phase that is designed to better characterize the safety, tolerability and preliminary anti-tumor 
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activity of the study drug when provided at the RP2D to patients with non-GCB subtype DLBCL 
with MYD88 L265P mutations. Phase 2 utilizes a Simon two-stage design, consisting of an 
open-label treatment of patients at the RP2D. Initially 10 patients will be treated at the RP2D. If 
at least two of the 10 patients respond, the study will enroll 19 more patients, for a total of 29 
patients in the Phase 2 portion. A schematic study design is represented in Figure 1. 
 
In Phase 1, each dose escalation cohort is expected to enroll at least three patients, with a maximum 
of six patients. The number of patients enrolled in any of the planned dose escalation cohorts can 
be reduced if safety at that dose level has already been demonstrated in a related population (e.g., 
WM) for following reasons: 1) If the initial three patients complete all 4 weeks of treatment without 
a DLT event, the DRC will conduct a dose escalation review; 2) If one of the initial three patients 
experiences a DLT event prior to completing Cycle 1, then enrollment at that dose level will 
continue to a total of six patients and the dose escalation review will be done when all six patients 
have completed Cycle 1; and 3) If two patients at a dose-level experience DLT events during the 
Cycle 1, then no further patients will be enrolled until the DRC completes a review, which should 
be done as soon as feasible. Furthermore, cohorts may be expanded to include additional patients 
if such patients can be enrolled ≤7 days after the third (or sixth) patient was first dosed with IMO-
8400. Screening will be done within 21 days prior to Cycle 1, Day 1 (the first treatment with study 
drug). The treatment is scheduled to be administered until disease progression, intolerable toxicity 
(despite dose modification), withdrawal of consent, start of another anti-cancer therapy, or study 
completion, whichever occurs first. Assessment for treatment response will continue throughout 
the patient’s participation or until disease progression. An EOT visit will be performed within 7 
days of the decision to terminate treatment. An EOS visit will be performed 30 to 35 days after the 
last dose of study drug. 
 
Figure 1: Study Schematic for 8400-402 
 
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4 
PHARMACOKINETIC ANALYSIS 
All pharmacokinetic analyses and generation of TLFs will be performed using a validated 
installation of Phoenix WinNonlin® version 6.4 (Pharsight, Cary, North Carolina USA) as part of 
a 21 CFR Part 11 compliant database system (Pharsight Knowledgebase Server “PKS”).  
4.1 
PK Population 
The primary analysis of PK will be conducted on the Pharmacokinetic (PK) Population which 
includes all patients who had both a pre-dose and at least one analyzable post-dose PK sample. 
 
4.2 
Blood Sampling Schedule 
4.2.1 
8400-401 
Pharmacokinetic samples (2 mL blood volume) will be obtained as scheduled in relation to first 
weekly dose administered on Day 1 of every cycle, at pre-dose and at 1 (± 5 minutes), 2 (± 10 
minutes), and 4 (± 15 minutes) hours post-dose. A PK sample will also be collected at the EOT 
and EOS visits. Plasma samples will be analyzed for IMO-8400 concentration using a validated 
bioanalytical method. Pharmacokinetic analysis will be conducted on an individual basis. The 
actual time and date of each blood draw will also be reported. 
 
4.2.2 
8400-402 
Pharmacokinetic samples (5 mL blood volume) will be obtained as scheduled in relation to the 
first dose administered at each of Cycles 1, 2, 4, and 6 (Day 1 of each cycle). The following PK 
samples will be collected: pre-dose, at 1 (±5 minutes), 2 (±10 minutes), and 4 (±15 minutes) hours 
post-dose. Pharmacokinetic samples will also be collected at the EOT and EOS visits. Plasma 
samples will be analyzed for IMO-8400 concentration using a validated bioanalytical method. 
 
4.3 
Pharmacokinetic Parameters 
4.3.1 
8400-401 
For each cohort, the plasma IMO-8400 concentration data will be analyzed by non-compartmental 
PK analysis. The following parameters (Table 3) will be determined as appropriate: observed 
maximum plasma concentration (Cmax), time of Cmax (Tmax), and AUC from 0 to last measurable 
plasma concentration (AUC0-t). Pharmacokinetic parameters will be compared across IMO-8400 
dose levels. Descriptive statistics will be provided for all PK parameter values by dose and time, 
as appropriate. 
 
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4.3.2 
8400-402 
For each cohort, the plasma IMO-8400 concentration data will be analyzed by non- compartmental 
PK analysis. The following parameters (Table 3) will be determined as appropriate: observed 
maximum plasma concentration (Cmax), time of Cmax (Tmax), and area under the curve from 0 to 
last measurable plasma concentration (AUC0-t). Pharmacokinetic parameters will be compared 
across IMO-8400 dose levels. Descriptive statistics will be provided for all PK parameter values 
by dose and time, as appropriate. 
 
 
Table 3. Planned Non-Compartmental PK Parameters. 
Parameter 
Description of Parameter 
Cmax 
Maximum observed concentration. 
Tmax 
Time of the maximum observed concentration. 
AUC0-t 
The area under the concentration time course profile from time = 0 (dosing) 
to the last quantifiable concentration (Ct) will be estimated using the linear 
trapezoidal rule follows: 
𝐴𝐴𝐴𝐴𝐴𝐴0−𝑡𝑡= ෍൤𝐶𝐶𝑖𝑖+1 + 𝐶𝐶𝑖𝑖
2
(𝑡𝑡𝑖𝑖+1 −𝑡𝑡𝑖𝑖)൨
𝑛𝑛−1
𝑖𝑖=1
 
Where Ci is the i-th sample, ti is the time of the i-th sample from dosing, and 
n is the number of available samples up to and including the final quantifiable 
concentration. 
 
AUC values will be estimated using the linear trapezoidal rule. Actual sampling times relative to 
dosing will be used in the computation.  
4.4 
Handling of Missing Sampling or Concentration Data 
Unless otherwise specified below, missing sampling or concentration values will not be imputed, 
but left missing in the calculation of derived PK parameters. Concentrations that are not reportable 
due to technical artifact or ambiguity (such as described in Section 4.6) will be treated as missing 
values. If the actual sampling time is missing, but a valid concentration value has been measured, 
the scheduled protocol time will be used for the calculation of derived PK parameters. A missing 
pre-dose value will be set to 0 for the PK calculations corresponding to an observation at dosing 
time (C0). 
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4.5 
Handling of Concentration Values below the Limit of Quantification (BLQ) 
For calculation of PK parameters, concentrations that are BLQ prior to or after the Tmax will be set 
to 0. For calculation of concentration summary (e.g., mean concentration), concentrations that are 
BLQ will be set to 0.  
4.6 
Handling of Outliers 
On a case by case basis, it may be necessary to exclude individual bioanalytical data from the 
calculation of derived PK parameters because they are erroneous, abnormal or appear implausible 
to the pharmacokineticist in charge of the analysis. Any excluded data will be flagged in the 
individual data listings. The reason for exclusion will also be documented. If the exclusion has a 
meaningful impact on the overall interpretation of the results, then it will be discussed. 
4.7 
Handling of Actual vs. Planned Sampling Timepoints 
Actual post-dose time will be used in calculation of PK parameters and in the generation of 
individual concentration-time profiles. Scheduled (nominal) sampling times will be used as a 
replacement for unknown or missing actual times and will be used for the pre-dose values. Nominal 
sampling times will also be used in the generation of summary concentration-time plots and tables  
4.8 
Handling of Individual Data and Summary Data Formats 
The actual values as provided from the bioanalytical laboratory will be displayed as individual 
concentration-time listings. Study drug concentrations will be used to calculate the following 
parameters: Cmax, Tmax, and AUC0-t, using non-compartmental analysis. For summary tables, the 
descriptive statistics will be rounded to one more digit than the individual values for the 
arithmetic mean, SD, median and geometric mean, and to the same number of digits for the 
minimum and maximum values. The Tmax will be reported using the median and range up to 2 
decimal points in listing and summary tables. The number of non-missing observations (N) will 
be reported as an integer number. The CV% and geometric CV% will be reported as a percentage 
of the integer number. 
5 
STATISTICAL METHODS 
5.1 
General Statistical Considerations 
Statistical analysis will be conducted by Kinder-Pharm LLC, using Phoenix WinNonlin 6.4 or 
newer version (Pharsight, Cary, North Carolina USA). 
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5.2 
Statistical Assessment 
A nonlinear power model will be used to assess the dose proportionality of IMO-8400 on day 1 of 
cycle 1 and cycle 2. The proportional relationship between exposure (Cmax, AUC0-t) and dose will 
be evaluated as a power model as follows: 
Parameter = A⋅doseB 
where A is a constant, B is the proportionality co-efficient, and the parameter is Cmax and          
AUC0-t. In conducting this analysis, the power model will be converted to a linear mixed effect 
model using natural logarithmic transformation as follows: 
ln(parameter) = ln(A) + B*ln(dose) 
 If the 90% confidence interval for the slope (B) includes 1.0, then the relationship will be 
considered to be dose proportional. 
6 
PRESENTATION OF RESULTS 
6.1 
Listings 
Individual time course values (nominal and actual sampling timepoints) and plasma IMO-8400 
concentrations will be listed for all subjects for each study separately (8400-401, and 8400-402). 
Individual IMO-8400 plasma PK parameter estimates from non-compartmental analysis will be 
listed for the PK Population. The PK parameters will include Cmax, and Tmax, and AUC0-t. 
6.2 
Tables 
Descriptive summary statistics (number of non-missing observations (N), arithmetic mean, 
standard deviation (SD), coefficient of variation (CV), median, minimum, maximum) will be 
reported for concentration profiles, grouped by each cohort (dose level) and each cycle (visit) and 
treatment for each study separately (8400-401 and 8400-402).  
 
Descriptive summary statistics (number of non-missing observations (N), arithmetic mean, 
standard deviation (SD), median, minimum, maximum, range, geometric mean and geometric 
CV% will be reported for PK parameters (Cmax, Tmax, and AUC0-t), grouped by cohort and each 
cycle (visit) for each study separately (8400-401, and 8400-402). All descriptive statistics will be 
reported for untransformed PK parameters. 
 
Geometric mean of Cmax and AUC0-t of cycle 1 day 1, and cycle 2 day 1 will be tabulated by dose 
to facilitate dose proportionality assessments. Dose-proportional power model analysis tables for 
Cmax and AUC0-t will be presented as the parameters Ln (A) and B, along with the respective 90% 
CIs. 
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6.3 
Figures 
Individual plots: The time course of IMO-8400 plasma concentration profile will be presented as 
one plot per graph and as composite plots for all subjects for each dose separately for each study 
separately (8400-401, and 8400-402). The graphical output will be presented in both linear and 
semi-log scales. Actual sampling times will be used for individual plots. 
 
Mean plots: For each study separately (8400-401, and 8400-402), the arithmetic mean of IMO-
8400 plasma concentration time profiles sorted by cohort and cycle will be presented in linear and 
semi-log graphs for each dose group. Linear mean plots will be presented with their upper SD bars. 
Scheduled (nominal) sampling times will be used for mean plots. 
 
Linear regression plot: Evaluable IMO-8400 Cmax and AUC0-t of cycle 1 and cycle 2 versus dose 
will be presented for each study separately (8400-401, and 8400-402). Linear regression line, R-
squared (Rsq), intercept, and slope will also be reported. 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
1.
REVISION HISTORY
3 
2.
DATA REVIEW COMMITTEE (DRC) MEMBERS
3 
3.
OBJECTIVE
4 
4.
PROTOCOL
4 
5.
RESPONSIBILITIES
4 
5.1 
INVESTIGATOR 
4 
5.2 
INC RESEARCH 
4 
5.3 
DATA MANAGEMENT (AXIOM) 
4 
5.4 
VERISTAT 
4 
5.5  
SPONSOR 
4 
6.
PREPARATION FOR DOSE ESCALATION MEETINGS
5 
7.
CONDUCT OF DOSE ESCALATION MEETINGS
5 
8.
OUTCOME OF DOSE ESCALATION MEETINGS
6 
9.
APPENDIX
           6 
9.1 APPENDIX 1 – INVESTIGATOR CONTACT LIST 
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1. REVISION HISTORY 
Version* 
Date 
Document Owner 
Revision Summary 
1.0 
07-Jul-2014 
Project Lead 
Initial Dose Escalation Procedure Plan 
2.0 
15-Sep-2014 
Project Lead 
Updated Data Review Committee Members Chart 
3.0 
23-Jun-2016 
Project Lead 
Added Revision History Table 
Updated signatories 
Addition of Veristat’s responsibilities 
Included anticipated outcomes from protocol 
Added appendix to list participating investigators 
* Note: Updates to appendices will be handled and filed independently and do not require an update 
and re-signing of the Dose Escalation Procedure Plan in its entirety. 
2. DATA REVIEW COMMITTEE (DRC) MEMBERS 
Affiliation 
Name / Position 
Contact Information 
Participating Investigators Please see Appendix 1 
Please see Appendix 1 
Medical Monitor 
Mark Cornfeld, MD 
VP & Medical Lead, Oncology 
Idera Pharmaceuticals, Inc. 
T: 484-348-1629 
M: 609-240-7312 
E: mcornfeld@iderapharma.com 
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3. OBJECTIVE  
The objective of this document is to establish the responsibilities and the procedure for handling of the 
patient safety data and the organization of the Data Review Committee (DRC) - to allow the Sponsor and 
participating investigators to evaluate preliminary safety data make a recommendation for the dose level 
to be used in the next cohort of patients, maximum tolerated dose (MTD) or other appropriate action.  
4. PROTOCOL  
Protocol Number: 8400-401 
Protocol Title: “A Phase 1/2 Open-label, Multiple-dose, Dose-escalation Study to Evaluate the Safety and 
Tolerability of IMO-8400 in Patients with Relapsed or Refractory Waldenström’s Macroglobulinemia”  
5. RESPONSIBILITIES 
5.1 
Investigator 
The primary responsibility of the Investigator at all times is the safety of the individual patient. Per 
protocol, the investigators responsibilities include the following:  
• Monitor patients for adverse events, including laboratory abnormalities, with particular attention to 
those meeting the criteria for a serious adverse event and dose-limiting toxicity (DLT) as defined 
in the protocol.   
• Document and enter study procedure and safety data in the Electronic Case Report Form (eCRF) 
in a timely manner, typically within 48 hours. All relevant eCRF pages (including safety pages) - 
for the patients that will be discussed during the upcoming dose escalation teleconference must 
completed within 48 hours after the last patient of the cohort has completed the DLT period. (i.e., 
received four weeks of treatment and completed the Week 5 visit procedures).  
• If requested, participate in the dose escalation teleconferences and provide patient updates. 
5.2 
INC Research 
• Monitor the sites at regular intervals and check the patient files with particular attention to safety 
data (CRA). Whenever possible, monitoring visits will be scheduled close to the upcoming DRC 
meeting so that as much of the data as possible has been monitored.   
• Organize the DRC meeting as close as possible to completion of DLT period of last patient in the 
cohort and provide the following support: schedule meeting date and time, prepare agenda, prepare 
meeting minutes, and file any related documents in the Electronic Trial Master File (eTMF).   
• The following INC Research project team members will participate in the DRC meeting: 
Project Manager, Lead CRA, Project Specialist. 
5.3 
Data Management (Axiom) 
• Distribute patient safety data listings to committee members. 
5.4 
Veristat 
• If necessary, provide patient safety data listings based on information available in the trial 
database in an agreed upon format at least 2 days prior to the scheduled DRC meeting. These 
listings may include data that has not yet been monitored.   
5.5 
Sponsor 
• Monitor subject eligibility by reviewing all screening data to confirm enrollment parameters are 
met.  
• Review of available patient safety data listings provided prior to each DRC meeting. 
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• Review/approval of the DRC meeting minutes before distribution to all participants. 
• The following Sponsor representatives who will participate in the DRC meeting include, but are 
not limited to: 
Idera Medical Monitor and Clinical Trial Manager 
• While the DRC will review data and make specific recommendations as detailed below, the final 
decision (e.g., dose escalate to the next higher dose level, de-escalate to a contingency dose level, 
or establish the MTD) will be made by Idera Pharmaceuticals, Inc and communicated by their 
representative.  
6. PREPARATION FOR DOSE ESCALATION MEETINGS 
The information needed for the DRC review includes the following elements:  
• Demographics 
• Inclusion Criteria 
• Exclusion Criteria 
• Dose Level Assignment 
• Dosing 
• Adverse Events 
• Injection Site Assessments 
• Concomitant Medications 
• Laboratory Assessments 
The INC PM or designee will perform the following:  
• Set a meeting date and time at least three weeks in advance 
• Prepare a meeting agenda, including the appropriate dial-in numbers and teleconference code.  
• Distribute the meeting agenda to all DRC attendees at least one week in advance. 
Axiom and/or Veristat will perform the following: 
• Prepare the data safety listings for distribution to all DRC members at least 48 hr prior to the 
meeting.  
7. CONDUCT OF DOSE ESCALATION MEETINGS 
DRC meetings will be scheduled per the dose escalation enrollment and review guidelines outlined in the 
protocol. The INC Project Manager (PM) will co-ordinate the DRC meetings. Each DRC member will 
have the opportunity to comment on the data presented, request additional data (if available), and offer 
their medical judgment regarding implications for the safety of patients enrolled in this study. As noted in 
the protocol, decisions regarding dose escalation will primarily be based on toxicities seen during the first 
four weeks of treatment to facilitate consistency across cohort, adverse events occurring beyond that 
period may be discussed and considered.  
The goal of the discussion is to reach a consensus recommendation regarding: 
• Review and provide definitive adjudication on individual DLTs, if needed 
• Perform dose-escalation review and make specific recommendations for the progress of the study 
• Determine the MTD / RP2D, or another dose for further exploration 
However, if consensus is not possible, then individual members may offer specific alternative 
recommendation(s) that are consistent with the protocol.  
The following represent anticipated outcomes for the review process: 
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• Dose escalation – progression to the next planned dose level. 
• Continue cohort enrollment (applicable only to review after 3 patients) – enroll up to 6 patients at 
the current dose level to obtain additional safety data for subsequent review. 
• Dose de-escalation – enrollment of intermediate dose levels for exploration of other schedules of 
administration. 
• Approve enrollment in an expansion cohort at a selected dose level, if applicable (see Section 6.4). 
• No further dose escalation enrollment – at this time the DRC will indicate the dose level that they 
consider represents the MTD. 
In the event that a principal investigator is not able to attend the DRC meeting, then that principal 
investigator may indicate agreement with the DRC outcome / decisions via email. Any agreements via 
email will be documented and filed with the DRC minutes. 
As noted above, the final decision remains the responsibility of Idera.  
8. OUTCOME OF DOSE ESCALATION MEETINGS 
Minutes will be prepared by INC Research PM/PC and shall include:  
• DLT events identified and confirmed by the DRC 
• Other treatment-related adverse events discussed by the DRC 
• The consensus recommendation and individual alternative recommendations, if any.  
The minutes will be provided to the Sponsor within 48 hours of the DRC meeting. The Sponsor will 
review the minutes, add their decision regarding study progression, and then distribute the minutes to all 
other attendees within another 48 hours. If the Sponsor’s decision diverges from the DRC 
recommendation, a follow-up conference call may be scheduled to permit further discussion.   
9. APPENDIX 
The appendix can be revised without the full review and written approval of the Dose Escalation 
Procedure. Appendix version control is required.
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9.1 
Appendix 1 – Investigator Contact List 
 
Site 
No 
Last Name 
First Name 
Company 
Business Address 
Business Phone 
Business Fax 
E-mail 
501 
Thomas 
Sheeba 
MD Anderson Cancer 
Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
713-792-2860 
713-744-5656 
sthomas@mdanderson.org 
504 
Harb 
Wael 
Horizon BioAdvance 
1345 Unity Place Suite 365 
Lafayette, IN 47905 
765-446-5165 
765-838-0972 
wharb@horizonbioadvance.com 
505 
Vesole 
David 
Hackensack Unviersity 
Medical Center 
92 Second Street 
Hackensack, NJ 07601 
551-996-8704 
551-996-0582 
dvesole@hackensackUMC.org 
506 
Ansell 
Stephen 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
507-284-2511 
507-284-5280 
ansell.stephen@mayo.edu 
509 
Beck 
Joseph 
Highlands Oncology Group 
3232 N. North Hills Blvd. 
Fayetteville, AR 72703 
479-587-1700 
479-587-1366 
tbeck@hogonc.com 
511 
Eradat 
Herbert 
UCLA Medical Center 
10945 Le Conte Ave., Suite 3360 
Los Angeles, CA 90095 
310-709-7741 
N/A 
heradat@mednet.ucla.edu 
512 
Heffner 
Leonard 
Emory University 
1365 Clifton Rd. Bldg. C Suite 3012 
Atlanta, GA 30322 
404-778-1900 
404-778-4389 
lheffne@emory.edu 
513 
Libby 
Edward 
Fred Huchison Cancer 
Center 
825 Eastlake Ave E. LV-200 
Seattle, WA 98109 
206-288-1453 
206-288-6549 
elibby@seattlecca.org 
 
INC Research® and Idera Pharmaceuticals 
CONFIDENTIAL and PROPRIETARY 
2008 INC RESEARCH®, Inc.  All rights reserved.  Reproduction or transmission to others apart from the parties involved with this document in any form or by any means is not permitted 
without the prior written consent of INC RESEARCH®, Inc. 
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