Clinical trial NCT03261999
Conditions: Prostatic Neoplasms
Keywords: Prostate Neoplasm Cancer Carcinoma
Sponsor: Foresee Pharmaceuticals Co., Ltd.
Start date: 2017-09-26; Completion date: 2019-02-01
Enrollment: 144 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study will evaluate if Leuprolide Mesylate is safe and effective in the treatment of subjects with prostate cancer, when administered as two injections twelve weeks apart.

Detailed description:
This is a multi-national, multi-center, open-label, single-arm study. All subjects will be males with prostate cancer judged to be candidates for medical androgen ablation therapy and all will receive two injections of LMIS 25 mg twelve-week apart in an unblinded fashion.

Arms: arm 1: All subjects will be males with prostate cancer. They will be injected twice with a depot formulation containing 25 mg of Leuprolide Mesylate.

The first dose on day 0 and the second dose on day 84 (twelve weeks apart). Subjects will be followed until day 168.
Interventions: intervention 1: Leuprolide Mesylate
Intervention descriptions: intervention 1: Subcutaneous injection of 25mg Leuprolide Mesylate

Protocol documents:
Prot_000.pdf: 
Foresee Pharmaceuticals Co., Ltd 
Confidential 
Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
1 
CLINICAL STUDY PROTOCOL 
An Open-Label, Single-Arm Study of the Efficacy, Safety, and Pharmacokinetic 
Behavior of Leuprolide Mesylate Injectable Suspension (LMIS 25 mg) in Subjects 
with Prostate Cancer 
Protocol No.: 
EudraCT No.: 
IND No.: 
Phase:  
Sites: 
Study Drug: 
Version: 
Date: 
Study Sponsor: 
FP01C-17-001 (NCT03261999)
2017-001333-88 
134405 
III 
Multi-national, Multi-Center 
Leuprolide Mesylate Injectable Suspension (LMIS 25 mg) 
1.1 
24 November 2017 
Foresee Pharmaceuticals Co., Ltd. 
3F., No. 19-3, Sanchong Rd., Nangang Dist. 
Taiwan, R.O.C. 
Contact: 
Telephone number: 
CRO Information: 
QPS, LLC 
3 Innovation Way, Ste. 240 
Newark, DE  19711 
CRO Services: 
Project Management, Monitoring, Data Management  
(OpenClinica-eCRF), Medical Writing, Bio-Statistics, Safety and BA Lab 
Medical Monitor: 
Contact number:  
Central Laboratory: 
Covance Central Laboratory 
Services Indianapolis 
8211 SciCor Drive 
Indianapolis, IN 46214 
Phone: +1-317-271-1200; Toll free: +1-800-462-8885 (USA only) 
Compliance of Guidance and/or Rules and Regulations 
This protocol is designed according to the International Conference on Harmonisation (ICH) guidance and the current 
national health authorities’ rules and regulations. The study will be conducted in accordance with the design and specific 
provisions of this Department of Health (DOH) and institutional review boards (IRBs) approved protocol, in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with Good Clinical 
Practice (GCP) and the applicable regulatory requirement(s). 




Foresee Pharmaceuticals Co., Ltd  
Confidential 
Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
3 
INVESTIGATOR’S SIGNATURE PAGE 
 
I understand my obligations as a clinical trial investigator and agree to perform and report the 
study in compliance with the protocol, Good Clinical Practice (GCP) and the current rules and 
regulations set forth by the applicable health authorities, regulations and the International 
Conference on Harmonisation (ICH). 
 
 
Name of Principal Investigator 
 
 
Title 
 
 
Signature 
 
 
Date 
 
 
 
 
  
  


Foresee Pharmaceuticals Co., Ltd  
Confidential 
Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
4 
PROTOCOL SYNOPSIS 
Ⅰ. Protocol title: 
An Open-Label, Single-Arm Study of the Efficacy, Safety, and Pharmacokinetic Behavior of 
Leuprolide Mesylate Injectable Suspension (LMIS 25 mg) in Subjects with Prostate Cancer 
Ⅱ. Objectives: 
LMIS 25 mg is the mesylate salt of leuprolide and has the same biological activity profile as 
leuprolide acetate salt. It is a luteinizing hormone-releasing hormone (LH-RH) agonist acting 
as a potent inhibitor of gonadotropin secretion when given in therapeutic doses, and lowers 
testosterone levels to castrate levels. Leuprolide is the standard of care for palliative treatment 
of prostate cancer. This study is designed to evaluate the safety, efficacy, and pharmacokinetic 
(PK) profile of LMIS 25 mg when given as two separate subcutaneous injections administered 
12 weeks apart in subjects with prostate cancer. 
1. Primary objective: 
To assess the efficacy and safety of LMIS 25 mg for up to 24 weeks following 2 subcutaneous 
doses given 12 weeks apart in subjects with prostate cancer  
2. Secondary objective: 
To establish a PK profile of serum leuprolide for LMIS 25 mg in a subset of subjects with 
prostate cancer 
Ⅲ. Study drug: 
1. Name: Leuprolide Mesylate Injectable Suspension (LMIS) 
2. Dosage form: Leuprolide extended release injectable suspension (US) or Leuprolide 
prolonged-release suspension for injection (EU), prefilled and supplied in 
one sterile syringe, ready-to-use  
3. Dose: 25 mg (as the mesylate salt) 
4.  Active ingredient: Leuprolide mesylate 
5. Dosing schedule: 25 mg leuprolide mesylate administered subcutaneously, when given as 
two separate injections at 12 weeks apart (Day 0 and Day 84). 
6.  Mechanism of action:  
The LH-RH agonist leuprolide, is known to inhibit pituitary gonadotropin secretion and 
suppress testicular and ovarian steroidogenesis. Continuous administration has been shown 
to maintain testosterone suppression. Serum testosterone concentrations in males have been 
reduced to levels associated with castration (≤ 50 ng/dL in serum). This effect is generally 
observed within two to four weeks after the start of treatment and is maintained as long as 
treatment continues. Induction and maintenance of castrate levels of serum testosterone in 
prostate cancer is a standard form of palliative treatment with a profound effect on cancer 
cell growth. LMIS 25 mg contains 25 mg leuprolide mesylate formulated in 
 and 
, to provide a 
sustained release of the bioactive leuprolide over a 3-month period after subcutaneous 


Foresee Pharmaceuticals Co., Ltd  
Confidential 
Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
5 
administration. 
7. Pharmacological category: Antineoplastic agent, gonadotropin releasing hormone analog 
Ⅳ. Developmental phase: phase □ Ⅰ □Ⅱ ■ Ⅲ □ Ⅳ □ Others 
Ⅴ. Study design: 
1.  □ Control: 
□ placebo 
□ active          
□ other           
■ Uncontrolled 
2.  Blinding: 
■ open-label   □ evaluator blind   □ single blind   □ double blind 
□ double dummy   □ other           
3.  Randomized:  □ yes    ■ no 
4.  □ Parallel   □ Cross-over   ■ Other Single-arm, open label 
5.  Duration of study: approx. 24 weeks 
6.  Titration:  □ forced   □ optional   ■ none 
7.  ■ Multi-national   ■ Multi-center   □ Single center 
Ⅵ. Endpoints 
1. Primary endpoint: 
 To determine the percentage of subjects with a serum testosterone concentration 
suppressed to castrate levels (≤ 50 ng/dL) on Day 28 ± 1 day (week 4) following 
administration of LMIS 25 mg, and the proportion of subjects with serum testosterone 
suppression (≤ 50 ng/dL) maintained from Day 28 ± 1 day (week 4) through Day 168 ± 5 
days (week 24)  
2. Secondary Endpoints: 
2.1 Efficacy: 
• 
The mean acute-on-chronic (surge) changes in testosterone and LH levels from just 
prior to the second injection through 14 days after the second injection of LMIS 25 mg 
(Day 98, week 14) 
• 
Effect of LMIS 25 mg on serum LH levels 
• 
Effect of LMIS 25 mg on serum prostate-specific antigen (PSA) levels 
• 
The percentage of subject with PSA relapse defined as after achieving the serum PSA 
level ≤ 4 ng/mL post LMIS 25 mg injection but with an increase in serum PSA of >50% 
PSA nadir by Day 168± 5 days (week 24) 
• 
The percentage of subject achieving normal serum PSA level (<4 ng/dL) on Day 168 ± 5 
days (week 24) 
• 
The percentage of subjects with enhanced serum testosterone concentration suppression 


Foresee Pharmaceuticals Co., Ltd  
Confidential 
Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
6 
to ≤ 20 ng/dL on Day 28 ± 1 day (week4) and on Day 168 ± 5 days (week 24) 
2.2 
Safety: 
• 
Adverse event (AE)/ serious adverse event (SAE) reporting 
• 
Assessment of injection site reaction 
• 
Change in bone pain measurement (by Visual Analogue Scale [VAS] scale) 
• 
Change in urinary signs and symptoms and total scores assessed by the International 
Prostate Symptom Score (I-PSS) sheet 
• 
Change in vital signs (BP, HR, RR, weight) 
• 
Change in physical examinations with clinical significance compared to baseline by 
principal investigator’s judgment 
• 
Change in lab data, including liver function (AST, ALT, ALP), renal function (BUN, SCr), 
complete blood count with platelets, clinical chemistries (K, Na, Mg, Ca and P), 
urinalysis, serum glucose, lipid profile (LDL, HDL, triglycerides) and HbA1c level 
• 
Clinically significant changes in 12-lead resting electrocardiogram (ECG) per the 
investigator’s judgment 
2.3 
Pharmacokinetic: 
• 
The serum pharmacokinetic profile of leuprolide for up to 26 weeks following 2 
subcutaneous injections of LMIS 25 mg given 12 weeks apart will be determined from 
baseline to Day 182 (week 26) in a subset of subjects. This subset of subjects will be 
followed for an additional two weeks to week 26 (Day 182) after the second injection. The 
PK parameters of leuprolide will be determined during the study period, including Cmax, 
Tmax, Cweek4, Cweek12, AUC0-week4, AUC0-week12, Cavg(0- week12) after each dose. 
2.4    Exploratory: 
• 
The PK/PD analysis (serum testosterone and leuprolide levels) in the first enrolled 30 
subjects on Day 182 (week 26) 


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Confidential 
Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
7 
Ⅶ. Selection criteria: 
1.  Main inclusion criteria: 
(1) Males aged ≥ 18 years old 
(2) Males with histologically confirmed carcinoma of the prostate  
(3) Subjects who are judged by the attending physician and/or principal investigator to 
be a candidate for androgen ablation therapy 
(4) Baseline morning serum testosterone level > 150 ng/dL performed at screening visit 
(5) Eastern Cooperative Oncology Group (ECOG) Performance score ≤ 2 
(6) Life expectancy of at least 18 months 
(7) Laboratory values 
o Absolute neutrophil count ≥ 1,500 cells/µL 
o Platelets ≥ 100,000 cells/µL 
o Hemoglobin ≥ 10 gm/dL 
o Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 
o AST (SGOT) ≤ 2.5 × ULN 
o ALT (SGPT) ≤ 2.5 × ULN 
o Serum creatinine ≤ 1.5 mg/dL 
o Lipid profile within acceptable range according to investigator’s opinion 
o Serum glucose within acceptable range according to investigator’s opinion 
o HbA1c ≤ 9.5% 
o Clinical chemistries (K, Na, Mg, Ca and P) within acceptable range according to 
Investigator’s opinion 
o Normal urinalysis results within: 
• RBCs ≤ 3 RBCs/hpf 
• WBCs ≤ 5 WBCs/hpf  
• Nitrate: negative 
• Glucose: <0.1 g/dL; but <1.0 g/dL in subjects with diabetes mellitus  
(8) Agree to use male contraceptive methods during study trial 
(9) In the investigator’s opinion, the ability to understand the nature of the study and any 
hazards of participation, and to communicate satisfactorily with the investigator and 
to participate in, and to comply with, the requirements of the entire protocol  
(10) All aspects of the protocol explained and written informed consent obtained 
2.  Main exclusion criteria: 


Foresee Pharmaceuticals Co., Ltd  
Confidential 
Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
8 
(1) Receipt 
of 
chemotherapy, 
immunotherapy, 
cryotherapy, 
radiotherapy, 
or 
anti-androgen therapy concomitantly, or within 8 weeks prior to screening visit, for 
treatment of carcinoma of the prostate. Radiation for pain control will be allowed 
during the study. 
(2) Receipt of any vaccination (including influenza) within 4 weeks of screening visit 
(3) History of blood donation within 2 months of screening visit 
(4) History of anaphylaxis to any LH-RH analogues 
(5) Receipt of any LH-RH suppressive therapy within 6 months of screening visit 
(6) Patients who were previously enrolled in the LMIS 50 mg study 
(7) Major surgery, including any prostatic surgery, within 4 weeks of screening visit 
(8) History and concomitant clinical and radiographic evidence of central nervous 
system/spinal cord metastases and subjects at risk for spinal cord compression 
(9) Clinical evidence of active urinary tract obstruction and subjects at risk for urinary 
obstruction 
(10) History of bilateral orchiectomy, adrenalectomy, or hypophysectomy 
(11) History or presence of hypogonadism; or receipt of exogenous testosterone 
supplementation within 6 months of screening visit 
(12) Clinically significant abnormal ECG and/or history of clinically significant 
cardiovascular disease as judged by the investigator 
(13) History of drug and/or alcohol abuse within 6 months of screening visit 
(14) Contraindication to leuprolide or an LH-RH agonist as indicated on package labeling 
(15) Use of 5-alpha reductase inhibitor within the last 6 months of screening visit 
(16) History or presence of insulin-dependent diabetes mellitus (Type I). Presence of well 
controlled diabetes mellitus Type II will be allowed if only oral hypoglycemic are 
required. Prostate cancer subjects with poor controlled diabetes mellitus with Hb1Ac 
> 9.5% or urine glycosuria > 1.0 g/dL should be excluded. 
(17) Use of systemic corticosteroids at a dose > 10 mg/d or anti-androgens  
(18) Use of any investigational agent within 4 weeks of screening visit 
(19) Use of any over-the-counter (OTC) medication within 4 weeks of screening visit 
except for those listed in the permitted Concomitant Treatment section 
(20) Uncontrolled intercurrent illness that would jeopardize the subject’s safety, interfere 
with the objectives of the protocol, or limit the subject’s compliance with study 
requirements, as determined by the investigator in consultation with the sponsor 
3.   Withdrawal criteria: 
(1) Lost to follow-up  
(2) Subject withdrew consent 


Foresee Pharmaceuticals Co., Ltd  
Confidential 
Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
9 
(3) In investigator’s opinion that treatment with prohibited medications is needed  
(4) Adverse event/serious adverse event  
(5) Protocol violation (please provide specific reason) 
(6) Lack of efficacy as determined by investigator 
(7) Subjects with persistent, non-castrate serum testosterone levels (>50 ng/dL)  
(8) Other 
Ⅷ. Study design: 
This is a multi-national, multi-center, open-label, single-arm study to determine the efficacy, 
safety, and pharmacokinetic profile of LMIS 25 mg in subjects with prostate cancer. The study 
duration is approximately 24 weeks. Two doses of LMIS 25 mg will be given to subjects by 
separate subcutaneous injection approximately 12 weeks apart in an unblinded manner. LMIS 
25 mg will be administered on Day 0 (Visit 2) and Day 84 (Visit 13; week 12). At the end of 
week 12 (Day 84), all subjects who have tolerated LMIS 25 mg will be administered the 
second dose of LMIS 25 mg and will be followed for tolerability, safety, efficacy, and PK/PD 
parameters for another 12 weeks (Day 168; week 24).  
Blood samples will be collected at baseline (Day 0) before LMIS 25 mg administration, 
immediately after LMIS 25 mg injection, and at specified time points to determine the 
pharmacokinetic (PK) and pharmacodynamics profiles of leuprolide and serum testosterone 
levels, respectively. The serum levels of testosterone, leuprolide, PSA, and luteinizing 
hormone (LH) will be measured during the study period. The PK parameters of leuprolide will 
be determined during the study period. 
The study period in the first enrolled 30 subjects (considered as a subset of subjects) will be 
extended for another 2 weeks post Day 168 (Day 182 ± 3 days; week 26; Visit 23) to obtain 
the extended PK/PD profile of serum leuprolide and testosterone levels. Approximately 133 
subjects will be enrolled in this study. 
All AEs and serious adverse events (SAEs) which occur during the study period will be 
recorded in the case report forms (CRFs) and followed until resolution or until they are 
considered stable. In addition, SAEs will be recorded and reported as required by both local 
and international regulatory requirements. 
For early-termination (ET) subjects, phone contacts should be performed at 12 weeks after 
the last injection of the investigational product to collect drug-related AEs, concomitant 
medication or non-drug therapy received for AE treatment, disease progression status, and 
subject survival status. 


Foresee Pharmaceuticals Co., Ltd  
Confidential 
Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
10 
Ⅸ. Concomitant treatment: 
1.  Permitted: 
(1) Bisphosphonates will be permitted during the study. 
(2) Denosumab will be permitted during the study. 
(3) Supplementation of vitamin D and calcium will be allowed during the study if, in the 
investigator’s opinion, it is needed for the subject’s health. 
(4) Plain, over-the-counter multi-vitamins will be permitted during the study. 
(5) Glucocorticosteroids will be allowed if being used as a replacement therapy. 
(6) Pain medication will be allowed if it is an over-the-counter or prescription medication 
as prescribed by a physician and meets the criteria outlined in Appendix IV. 
(7) Oral hypoglycemics will be allowed for control of Type II diabetes. 
(8) Radiation for pain control will be allowed during the study. 
2.  Prohibited: 
The medications below are prohibited during the treatment period: 
(1) Other gonadotropin-releasing hormones 
(2) Other chemotherapy, immunotherapy, cryotherapy, radiotherapy for treatment of 
prostate carcinoma 
(3) Any OTC medication other than those listed in the Concomitant Treatment section 
(4) Dietary supplements, herbal supplements, or herbal tea 
(5) Insulin 
(6) Anti-androgens 
(7) 5-alpha reductase inhibitors 
(8) Systemic corticosteroids > 10 mg/d 
Ⅹ. Statistics: 
1.  Primary hypothesis: □ superiority 
 
□ non-inferiority 
 
 
 
 
 
    □ equivalence ■ other  
2.  Sample size : Approximately 133 subjects will be enrolled. It is anticipated that > 100 
subjects will receive 2 separate doses of LMIS 25 mg given at 12 weeks apart. A 10% 
drop out rate is estimated. 
3.  Efficacy population:  ■ ITT   ■ PP   □ other:  
(1) The Intention-To-Treat (ITT) population will consist of any subject receiving at least 
one dose of LMIS 25 mg. 
(2) The Per Protocol (PP) population will be composed of those subjects who received 2 
doses of LMIS 25 mg without major deviations that will impact the assessment of the 


Foresee Pharmaceuticals Co., Ltd  
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Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
11 
primary efficacy endpoint.   
4. Safety population:   □ ITT   □ PP   ■ other: 
The safety population will consist of any subject receiving a dose of LMIS 25 mg. 
5. Statistical method(s) for efficacy/ safety evaluations: 
(1) The ITT and PP populations will be used in the efficacy analyses. Any subject 
receiving a dose of LMIS 25 mg will be included in the safety analysis.  
(2) For descriptive statistics, continuous variables will be presented as number of 
observations, mean, standard deviation (SD), median, range, Hodges-Lehmann 
estimator and 95% CI. Categorical variables will be presented by frequency and 
percentage. Changes from baseline will be tested by a paired t-test or Wilcoxon 
signed-rank test for continuous variables using a significance level of 0.05. 
(3) For primary endpoints, the percentage of subjects with a serum testosterone of ≤ 50 
ng/dL (castrate level) on Day 28 ± 1 day (week 4) and on Day 168 ± 5 days (week 24) 
will be analyzed using a standard large sample approximation to a Binomial 
distribution. The percentage of subjects with a serum testosterone of ≤50 ng/dL (castrate 
level) from Day 28 ± 1 day (week 4) through Day 168 ± 5 days (week 24) will be 
analyzed using the Kaplan-Meier approach. 
(4) The following efficacy analyses will be provided in detail in the statistical analysis plan: 
• 
The proportion of subjects with testosterone suppression (≤ 50 ng/dL) from Day 
28 (week 4) through Day 168 ± 5 days (week 24)  
• 
Subjects exhibiting post-suppression breakthrough of serum testosterone to >50 
ng/dL 
• 
Time to event: A subject with a testosterone level > 50 ng/dL between Days 28 
and 168 is considered to have an event.   
(5) The mean acute-on-chronic (surge) changes in serum testosterone level and LH level 
will be summarized by descriptive statistics; the change from the baseline levels of 
testosterone and LH post the second injection of LMIS 25 mg will be summarized 
descriptively. 
(6) The serum PSA levels and serum LH levels during the study will be summarized by 
descriptive statistics, and the change from baseline will also be summarized 
descriptively and a paired t-test or Wilcoxon signed-rank test will be used, data 
significance level of 0.05. 
(7) The PSA relapse is defined as any subjects who achieve the serum PSA level ≤ 4 ng/mL 
post LMIS 25 mg injection but then have an increase in serum PSA of >50% PSA nadir 
by Day 168 (week 24). This endpoint will be presented as a count, percentage and 95% 
CI. 
(8) The percentage of subjects with an enhanced serum testosterone ≤ 20 ng/dL by Day 28 
± 1 day (week 4) and Day 168 ± 5 days (week 24) will be analyzed using a standard 
large sample normal approximation to a Binomial distribution. 


Foresee Pharmaceuticals Co., Ltd  
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Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
12 
(9) For safety assessment, the local injection site reaction will be summarized descriptively. 
(10) The summary results at baseline (Day 0) and the change of continuous variables 
including bone pain measurement (by VAS scale), urinary signs and symptoms (by the 
I-PSS sheet), vital signs and lab data will be summarized descriptively, and a paired 
t-test or Wilcoxon signed-rank test will be used at a significance level of 0.05. The 
transition matrix for categorical variables will be presented. 
(11) AEs will be coded with MedDRA, and a summary frequency table of AEs will be 
provided. The severity and relationship to study medication of AEs will be summarized 
as well. Furthermore, if any SAE occurs, a summary of SAEs will be presented and 
listed in tables. 
(12) For PK profile analysis, arithmetic means, standard deviations (SDs) and coefficients 
of variation (CV) will be calculated. 
(13) All statistical tests will be two-sided and evaluated at the 0.05 level of significance. 
6. Planned interim analysis: □yes     ■no 
 
 
 


Foresee Pharmaceuticals Co., Ltd  
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Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
13 
Table 1a. Study Schedule: VISITS 1-13 
 
 
Scrn 
1st Dose 
Follow Up 
2nd Dose 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
 
1 
1 
1 
1 
1 
2 
3 
4 
6 
8 
11 
12 
12 
12 
12 
Day 
-28 to 
-1 
0 
1 
2 
3 
7 
14 
21 
28 
42# 
56 
77 
84* 
Hour 
 
0 
2 
4 
8 
 
 
 
 
 
 
 
 
 
 
0 
2 
4 
8 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject screening number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject enrollment number 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor history1/Medical and 
medication 
history2/comorbidity 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant treatments2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X 
X 
X 
Physical examination3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Vital signs4 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
 
 
 
ECOG PS 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG5 
X 
X 
 
X5 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X5 
 
Study treatment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Local injection site reaction 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Adverse event/SAE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X 
X 
X 
Hormone level 
Testosterone6 
X 
X 
X# 
X 
X# 
X 
X# 
X  
X# 
X 
X 
X 
X# 
X 
X 
X 
X# 
X 
X# 
Luteinizing hormone7 
X 
X 
 
 
 
X 
X# 
X 
X# 
X 
X 
X 
X# 
X 
X 
X 
 
 
 


Foresee Pharmaceuticals Co., Ltd  
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Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
14 
 
Scrn 
1st Dose 
Follow Up 
2nd Dose 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
 
1 
1 
1 
1 
1 
2 
3 
4 
6 
8 
11 
12 
12 
12 
12 
Day 
-28 to 
-1 
0 
1 
2 
3 
7 
14 
21 
28 
42# 
56 
77 
84* 
Hour 
 
0 
2 
4 
8 
 
 
 
 
 
 
 
 
 
 
0 
2 
4 
8 
Lab chemistry 
Hematology8/ Biochemistry9 
X/X 
X/X 
 
 
 
 
 
 
 
X/X 
 
X/X 
 
 
 
X/X 
 
 
 
Pharmacokinetic 
serum 
sample 
for 
leuprolide 
mesylate (LM) 
 
X 
X# 
X 
X# 
X 
X# 
X 
X# 
X 
X 
X 
X# 
X 
X 
X 
X# 
X 
X# 
PSA 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Urinalysis10 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone pain (VAS)/ Urinary 
signs and symptoms (I-PSS) 
 
X/X 
 
 
 
X/X 
 
 
X/X X/X 
 
X/X 
 
X/X 
 
X/X 
 
 
 
Abbreviation: Baseline: Day 0; AE: Adverse Event; BT: Body temperature; ECG: Electrocardiogram; ECOG PS: Eastern Cooperative Oncology 
Group Scale of Performance Status; EOS: end of study; ET: early termination; HbA1c: glycosylated hemoglobin; HR: Heart rate; LH: luteinizing 
hormone; PD: Pharmacodynamic(s); PK: Pharmacokinetic(s); PSA: Prostate Specific Antigen; RR: Respiratory rate; Scrn: Screening; BP: Blood 
pressure; VAS: Visual Analogue Scale; I-PSS: International Prostate Symptom Score (I-PSS) 
* 
If the subject cannot return on Day 84 (the second dose, Visit 13), please have the subsequent visits on Days 85, 86, 87, 98, and 112 to be 
scheduled according to the actual occurred date of the Day 84 visit. For the Day140 Visit (Visit 20), adjust the scheduled date according to the date 
when the first injection was received. 
# Procedures/examinations for the first enrolled 30 subjects only. 
1 Cancer/tumor history should be recorded in a life-time basis. 
2 Medical and medication history (including procedural and surgical history, blood donations, and vaccinations) will be recorded up to 6 months 
prior to screening visit. Concomitant medication use will be recorded up to 6 months prior to screening visit. 
3 Height will be only measured at screening visit. Weight will be measured at screening visit, Day 84, and Day 168 (EOS/ET). 
4 Vital signs include BP, HR, RR, and BT. 
5 12-lead ECG monitoring will be performed at specified time points. When 12-lead ECG has to be performed on dosing days, it will be performed 
prior dosing and at 4-hour post LMIS 25 mg injection in all subjects on dosing days (Days 0 and Day 84). 
6 Testosterone samples will be collected in the morning at specified time points as shown in the above schedule. On dosing days (Day 0 and Day 
84), blood samples for testosterone analysis will be collected before LMIS 25 mg administration. Serum testosterone levels will be analyzed at 
the QPS Bioanalytical Lab. For fast turn-around of assay results, a sample for the screening testosterone will also be sent to the Central Lab. After 


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Protocol No.: FP01C-17-001 
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15 
that, additional samples for testosterone may be ordered by the investigator at their discretion and done at the Central Lab using commercial 
diagnostic assays for fast turn-around of results. 
7 LH samples will be collected in the morning at specified time points as shown in the above schedule. On dosing days (Day 0 and Day 84), blood 
samples for LH analysis will be collected before LMIS 25 mg administration. Serum samples for LH concentrations will be analyzed at the BA 
lab using a validated ELISA method. More frequent tests of LH may be ordered by the investigators at their discretion, and these samples can 
be analyzed at the Central Lab for a faster data turn-around. Serum samples to the BA Lab will be batched and shipped periodically. 
8 Hematology tests include CBC, Hb, Hct, RBC count, WBC count with differential, and platelet count. 
9 Biochemistry tests include ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, Mg, Ca and P), blood glucose, and lipid profile 
(LDL, HDL, triglycerides). 
10 Urinalysis tests include pH, specific gravity, leukocyte, erythrocyte, urine glucose, nitrate, and protein. 
Note: Regarding the time window for blood sample collection, at 2, 4, 8 hours post LMIS 25 mg administration on Day 0 (Visit 1) and 
Day 84 (Visit 13), a 15-minute time window is allowed ; at Visits 6 to 9 (Day 7 to Day 28, week 4), a ± 1-day window is allowed. At 
Visits 10 and 12 (Day 42 to Day 77; week 6 to week 11), a ± 3-day window is allowed. At Visits 13 to 16 (Day 84 for the second dose 
injection, week 12 to Day 87), only ± 1-day window is allowed. At Visits 17 to 21 (Day 98 to Day 161), a ± 3-day window is allowed. 
At Visit 22 (Day 168), a ± 5-day window is allowed. At Visit 23 (Day 182), a ± 3-day window is allowed. 
 
 
 


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Table 1b Study Schedule: VISITS 14-EOS/ET (Visit 22 or 23) 
 
 
Follow Up 
EOS/ET PK-extended 
Follow up 
Visit 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23# 
Week 
13 
13 
13 
14 
16 
18 
20 
23 
24 
26 
Day 
85* 
86* 
87* 
98* 
112* 
126# 
140 
161 
168 
182# 
Concomitant treatments2 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X# 
Physical examination3 
 
 
 
 
 
 
 
 
X 
 
Vital signs4 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X# 
ECOG PS 
 
 
 
 
 
 
 
 
 
 
12-lead ECG5 
 
 
 
 
 
 
 
 
X 
 
Study treatment 
 
 
 
 
 
 
 
 
 
 
Local injection site reaction 
X 
X 
 
 
 
 
 
 
 
 
Adverse event/SAE 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X# 
Hormone level 
Testosterone6 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X# 
Luteinizing hormone7 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
 
Lab chemistry 
Hematology8/ Biochemistry9 
 
 
 
 
 
 
 
 
X/X 
 
Pharmacokinetic serum sample for leuprolide mesylate 
(LM) 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X# 
PSA 
 
 
 
 
 
 
 
 
X 
 
Urinalysis10 
 
 
 
 
 
 
 
 
X 
 
HbA1c 
 
 
 
 
 
 
 
 
X 
 
Bone pain (VAS) /Urinary sign and symptoms (I-PSS) 
 
 
 
 
X/X 
 
X/X 
 
X/X 
 
Abbreviation: Baseline: Day 0; AE: Adverse Event; BT: Body temperature; ECG: Electrocardiogram; ECOG PS: Eastern Cooperative 
Oncology Group Scale of Performance Status; EOS: end of study; ET: early termination; HbA1c: glycosylated hemoglobin; HR: 
Heart rate; LH: luteinizing hormone; PD: Pharmacodynamic(s); PK: Pharmacokinetic(s); PSA: Prostate Specific Antigen; RR: 


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Respiratory rate; Scrn: Screening; BP: Blood pressure; VAS: Visual Analogue Scale; I-PSS: International Prostate Symptom Score 
(I-PSS) 
* If the subject cannot return on Day 84 (the second dose, Visit 13), please have the subsequent visits on Days 85, 86, 87, 98, and 112 
to be postponed according to the actual occurred date of the Day 84 visit. For the Day140 Visit (Visit 20, week 20), adjust the 
scheduled date according to the date when the first injection was received 
 For early termination subjects (ET), end of study (EOS) procedure and examination should be performed on that day. In addition, 
phone contacts should be performed at 12 weeks after the last injection of investigational product to collect drug-related AE, 
concomitant medication or non-drug therapy received for AE treatment, disease progression status, and subject survival status. 
# Procedures/ examinations for the first enrolled 30 subjects only. 
2 Concomitant medication use will be recorded up to 6 months prior to screening visit. 
3 Height will be only measured at screening visit. Weight will be measured at screening, Day 84, and Day 168 (EOS/ET). 
4 Vital signs include BP, HR, RR, and BT. 
5 12-lead ECG monitoring will be performed at specified time points. 
6 
.Testosterone samples will be collected in the morning at specified time points as shown in the above schedule. Serum testosterone 
levels will be analyzed at the QPS Bioanalytical Lab.  
7 LH samples will be collected in the morning at specified time points as shown in the above schedule. On dosing days (Day 0 and 
Day 84), blood samples for LH analysis will be collected before LMIS 25 mg administration. Serum samples for LH concentrations 
will be analyzed at the BA lab using a validated ELISA method. More frequent tests of LH may be ordered by the investigators at 
their discretion, and these samples can be analyzed at the Central Lab for a faster data turn-around. Serum samples to the BA Lab 
will be batched and shipped periodically. 
8 Hematology tests include CBC, Hb, Hct, RBC count, WBC count with differential and platelet count. 
9 Biochemistry tests include ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, Mg, Ca and P), blood glucose, and 
lipid profile (LDL, HDL, triglycerides). 
10 Urinalysis tests include pH, specific gravity, leukocyte, erythrocyte, urine glucose, nitrate, and protein. 
Note: Regarding the time window for blood sample collection, at 2, 4, 8 hours post LMIS 25 mg administration on Day 0 
(Visit 1) and Day 84 (Visit 13), a 15-minute time window is allowed; at Visits 6 to 9 (Day 7 to Day 28), a ± 1-day window 
is allowed. At Visits 10 and 12 (Day 42 to Day 77), a ± 3-day window is allowed. At Visits 13 to 16 (Day 8 for the second 
dose injection, week 12, to Day 87), only ± 1-day window is allowed. At Visits 17 to 21 (Day 98 to Day 161), a ± 3-day 
window is allowed. At Visit 22 (Day 168), a ± 5-day window is allowed. At Visit 23 (Day 182), a ± 3-day window is 
allowed. 
 
 
 


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TABLE OF CONTENTS 
INTERNAL SIGNATURE PAGE .................................................................................................. 2 
INVESTIGATOR’S SIGNATURE PAGE ..................................................................................... 3 
PROTOCOL SYNOPSIS ................................................................................................................ 4 
TABLE 1A. STUDY SCHEDULE: VISITS 1-13 ......................................................................... 13 
TABLE 1B STUDY SCHEDULE: VISITS 14-EOS/ET (VISIT 22 OR 23) ................................ 16 
TABLE OF CONTENTS ............................................................................................................... 18 
TABLE OF TABLES .................................................................................................................... 22 
LIST OF ABBREVIATIONS AND TERMS ................................................................................ 23 
1. 
INTRODUCTION ...................................................................................................... 26 
1.1. 
Background Information ............................................................................................. 26 
1.2. 
The Development of Leuprolide Acetate ................................................................... 26 
1.3. 
Study Rationale ........................................................................................................... 26 
2. 
STUDY OBJECTIVE AND ENDPOINTS ................................................................ 29 
2.1. 
Study Objective .......................................................................................................... 29 
2.1.1. 
Primary objective ........................................................................................................ 29 
2.1.2. 
Secondary objective .................................................................................................... 29 
2.2. 
Study Endpoints .......................................................................................................... 29 
2.2.1. 
Primary endpoints ....................................................................................................... 29 
2.2.2. 
Secondary endpoints ................................................................................................... 29 
3. 
STUDY DESIGN ....................................................................................................... 31 
3.1. 
Overall Design ............................................................................................................ 31 
4. 
ELECTION AND WITHDRAWAL OF SUBJECTS ................................................ 33 
4.1. 
Inclusion Criteria ........................................................................................................ 33 
4.2. 
Exclusion Criteria ....................................................................................................... 34 
4.3. 
Withdrawal Criteria .................................................................................................... 35 
5. 
STUDY TREATMENT .............................................................................................. 36 
5.1. 
Treatment Plan Summary ........................................................................................... 36 
5.2. 
Treatment Assignment ................................................................................................ 36 
5.3. 
Description of Study Drug .......................................................................................... 36 
5.4. 
Rationale for Dose ...................................................................................................... 36 


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5.5. 
Warning and Precautions ............................................................................................ 37 
5.6. 
Packaging and Labeling .............................................................................................. 37 
5.7. 
Supply, Delivery, Storage of Study Drug ................................................................... 38 
5.8. 
Drug Dispensation and Accountability ....................................................................... 38 
5.9. 
Treatment Exposure and Compliance ......................................................................... 38 
5.10. 
Treatment for Investigational Product Overdose ........................................................ 38 
6. 
STUDY PROCEDURES ............................................................................................ 39 
6.1. 
Screening Visit 1 (Day -28 ~ -1) ................................................................................ 45 
6.2. 
Visit 2 (Day 0; 1st Dose Administration) .................................................................... 46 
6.3. 
Visit 3 (Day 1) ............................................................................................................ 46 
6.4. 
Visit 4 (Day 2) ............................................................................................................ 47 
6.5. 
Visit 5 (Day 3) ............................................................................................................ 47 
6.6. 
Visit 6 (Day 7 ± 1 day, week 1) .................................................................................. 47 
6.7. 
Visit 7 (Day 14 ± 1 day, week 2) ................................................................................ 47 
6.8. 
Visit 8 (Day 21 ± 1 day, week 3) ................................................................................ 48 
6.9. 
Visit 9 (Day 28 ± 1 day, week 4) ................................................................................ 48 
6.10. 
Visit 10 (Day 42 ± 3 days, week 6-for the first enrolled 30 subjects only) ................ 49 
6.11. 
Visit 11 (Day 56 ± 3 days, week 8) ............................................................................ 49 
6.12. 
Visit 12 (Day 77 ± 3 days, week 11) .......................................................................... 49 
6.13. 
Visit 13 (Day 84 ± 1 day; 2nd Dose Administration; week 12) .................................. 49 
6.14. 
Visit 14 (Day 85 ± 1 day, week 13) ............................................................................ 50 
6.15. 
Visit 15 (Day 86 ± 1 day; week 13) ............................................................................ 50 
6.16. 
Visit 16 (Day 87 ± 1 day; week 13) ............................................................................ 51 
6.17. 
Visit 17 (Day 98 ± 3 days, week 14) .......................................................................... 51 
6.18. 
Visit 18 (Day 112 ± 3 days, week 16) ........................................................................ 51 
6.19. 
Visit 19 (Day 126 ± 3 days; week 18 for the first enrolled 30 subjects only) ............ 51 
6.20. 
Visit 20 (Day 140 ± 3 days; week 20) ........................................................................ 52 
6.21. 
Visit 21 (Day 161 ± 3 days, week 23) ........................................................................ 52 
6.22. 
Visit 22 (Day 168 ± 5 days/EOS/ ET; week 24) ........................................................ 52 
6.23. 
Visit 23 (Day 182 ± 3 days/PK-extended follow up; week 26) .................................. 53 
7. 
STUDY ASSESSMENTS .......................................................................................... 54 
7.1. 
Screening Assessment ................................................................................................ 54 
7.1.1. 
Informed consent form ............................................................................................... 54 


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7.1.2. 
Demographics / history ............................................................................................... 54 
7.1.3. 
Eligibility .................................................................................................................... 55 
7.1.4. 
ECOG performance status .......................................................................................... 55 
7.2. 
Efficacy Assessment ................................................................................................... 55 
7.2.1. 
Hormone level ............................................................................................................ 56 
7.2.2. 
PSA level .................................................................................................................... 57 
7.3. 
Safety Assessment ...................................................................................................... 57 
7.3.1. 
Physical examinations and vital signs ........................................................................ 57 
7.3.2. 
Local injection site reaction assessment ..................................................................... 57 
7.3.3. 
Hematological / biochemistry examinations .............................................................. 58 
7.3.4. 
Urinalysis .................................................................................................................... 59 
7.3.5. 
ECG ............................................................................................................................ 59 
7.3.6. 
Bone pain .................................................................................................................... 59 
7.3.7. 
Urinary signs and symptoms ...................................................................................... 59 
7.3.8. 
Adverse events ............................................................................................................ 59 
7.4. 
Pharmacokinetics Assessment .................................................................................... 60 
7.4.1. 
Pharmacokinetic assessments of LMIS 25 mg ........................................................... 60 
7.4.2. 
Serum sample analysis for Leuprolide Mesylate ........................................................ 60 
7.4.3. 
Pharmacokinetic analysis of Leuprolide Mesylate ..................................................... 60 
8. 
CONCOMITANT TREATMENT ............................................................................. 61 
8.1. 
Permitted Treatment ................................................................................................... 61 
8.2. 
Prohibited Treatment .................................................................................................. 61 
8.3. 
Rescue Medication and Treatment ............................................................................. 62 
9. 
SAFETY MONITORING .......................................................................................... 63 
9.1. 
Adverse Events ........................................................................................................... 63 
9.1.1. 
The severity grade of AEs .......................................................................................... 63 
9.1.2. 
The relationship to study drug .................................................................................... 64 
9.2. 
Serious Adverse Events .............................................................................................. 65 
9.3. 
Serious Adverse Events Reporting Requirement and Emergency Procedures ........... 65 
9.4. 
Pregnancies ................................................................................................................. 66 
10. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ....................... 67 
10.1. 
Sample Size ................................................................................................................ 67 
10.2. 
Analysis Population .................................................................................................... 67 


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10.3. 
Analysis Method ......................................................................................................... 67 
10.4. 
Efficacy Analysis ........................................................................................................ 67 
10.4.1. 
Analysis of primary endpoint ..................................................................................... 67 
10.4.2. 
Analysis of secondary endpoints ................................................................................ 68 
10.5. 
Safety Analysis ........................................................................................................... 70 
10.6. 
Pharmacokinetics Analysis ......................................................................................... 71 
10.7. 
Handling of Missing Values ....................................................................................... 72 
11. 
STUDY ADMINISTRATIVE STRUCTURE ........................................................... 73 
11.1. 
Ethical Conduct of the Study ...................................................................................... 73 
11.2. 
Institutional Review Board (IRB) / Ethics Committee (EC) ...................................... 73 
11.3. 
Informed Consent Process and Subject Information .................................................. 73 
12. 
INSURANCE AND INDEMNITY ............................................................................ 74 
13. 
SOURCES DOCUMENTS ........................................................................................ 75 
14. 
CASE REPORT FORM ............................................................................................. 76 
15. 
CONTROL AND ASSURANCE OF STUDY QUALITY ........................................ 77 
15.1. 
Assignment of Site Monitor ....................................................................................... 77 
15.2. 
Data Quality Assurance .............................................................................................. 77 
15.3. 
Audits and Inspections ................................................................................................ 77 
16. 
PROTOCOL DEVIATION / VIOLATION ............................................................... 78 
17. 
PROTOCOL AMENDMENTS .................................................................................. 79 
18. 
COMPLETION OF STUDY ...................................................................................... 80 
19. 
TERMINATION OF STUDY .................................................................................... 81 
20. 
RETENTION OF RECORDS AND CONFIDENTIALITY ...................................... 82 
21. 
USE OF INFORMATION AND PUBLICATION .................................................... 83 
22. 
REFERENCES ........................................................................................................... 84 
APPENDIX I ................................................................................................................................. 86 
APPENDIX II ................................................................................................................................ 90 
APPENDIX III ............................................................................................................................... 91 
APPENDIX IV .............................................................................................................................. 93 
ENDNOTES .................................................................................................................................. 97 
LITERATURE: .............................................................................................................................. 97 
 
 
 


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TABLE OF TABLES 
Table 1a 
Study Schedule Visits 1-13 ......................................................................................... 40 
Table 1b 
Study Schedule Visits 14-EOS ................................................................................... 43 
Table 2 
Grading of local injection reaction ............................................................................. 58 
Table 3 
Intensity Scales of Adverse Events ............................................................................ 64 
Table 4 
The Relationship between Adverse Events and Occurrence ...................................... 64 
Table 5 
Data Censoring Rules ................................................................................................. 69 
Table 6 
Pharmacokinetic analysis of leuprolide mesylate in all subjects ................................ 71 


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LIST OF ABBREVIATIONS AND TERMS 
TERM 
DEFINITION 
ADL 
Activities of Daily Living 
ADR 
Adverse Drug Reactions 
ADT 
Androgen Deprivation Therapy 
AE(s) 
Adverse Event(s) 
ALT (SGPT) 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
ANC 
Absolute Neutrophil Count 
Approx. 
Approximately 
AST (SGOT) 
Aspartate Transaminase 
BDM 
Biostatistics & Data Management 
BLQ 
Below Limit of Quantitation 
BP 
Blood Pressure 
BT 
Body Temperature 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CRC 
Clinical Research Coordinator 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
EC 
Ethics Committee 
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
ENT 
Ear, Nose, and Throat 
ET 
Early Termination 
EOS 
End of Study 
FDA 
Food and Drug Administration 


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TERM 
DEFINITION 
F/U 
Follow-up 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GnRH 
Gonadotropin-Releasing Hormone 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HDL 
High Density Lipoprotein 
hpf 
High power field 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IP 
Investigational Product 
I-PSS 
International Prostate Symptom Score  
IRB 
Institutional Review Board 
IS 
Internal Standard 
ITT 
Intent-to Treat 
IV 
Intravenously 
K 
Potassium 
LC/MS/MS 
Liquid Chromatography-tandem Mass Spectrometry 
LDL 
Low Density Lipoprotein 
LH 
Luteinizing Hormone 
LH-RH 
Luteinizing Hormone-Releasing Hormone 
LMIS 
Leuprolide Mesylate Injectable Suspension 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Magnesium 
Na 
Sodium 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NMP 
N-methyl-2-pyrrolidone 
OTC 
Over-the-Counter 
P 
Potassium 
PD 
Pharmacodynamics 
PI 
Principal Investigator 


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TERM 
DEFINITION 
PK 
Pharmacokinetics 
PLA 
Poly (D, L-lactide) 
PLGA 
Poly (D, L-lactide-co-glycolide) 
PP 
Per-Protocol 
PR 
Partial Response 
PS 
Performance Status 
PSA 
Prostate Specific Antigen 
QC 
Quality Control 
RBC 
Red Blood Cell 
RR 
Respiratory Rate 
SAE(s) 
Serious Adverse Event(s) 
SBP 
Systolic Blood Pressure 
SCr 
Serum Creatinine 
Scrn 
Screening 
SOC 
System Organ Class 
SOP 
Standard Operation Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Total Bilirubin 
TEAE 
Treat emergent adverse event 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
1.1. 
Background Information 
Prostate cancer is one of the leading causes of deaths in men globally. [1, 2]. In the absence of 
screening, disease progression of prostate cancer is asymptomatic in early stages and therefore, it is 
often diagnosed late. More than 90% of prostate tumors are found locally or regionally. Men aged 
65 years or older are the major group at risk; other common risk factors include ethnicity, family 
history, dietary habits, smoking, and occupational exposure. Since 1990, the use of molecular 
screening methods has greatly increased the diagnosis rate and the percentages of patients 
receiving early treatments [3]. 
Therapeutic choice for the treatment of prostate cancer is determined based on age, tumor grade 
and stage as well as other medical conditions. In conjunction with radiation and chemotherapy, 
hormonal therapy is widely used in the treatment of prostate cancer patients. Recent evidence has 
suggested that disease progression of prostate cancer is highly dependent on androgen levels. Long 
term hormonal control helps to alleviate the growth of proliferating prostate cancer cells and may 
be beneficial to patient survival [4,5]. On this basis, the development of androgen deprivation 
therapy (ADT) has been the mainstay of hormonal treatment for prostate cancer over the years. 
Thus, various types of pharmaceutical agents have been developed to produce the effect of medical 
castration. These agents include gonadotropin-releasing hormone (GnRH) agonist, GnRH 
antagonist, estrogen agonist, and androgen inhibitors [6,7,8]. 
1.2. 
The Development of Leuprolide Acetate 
Chronic administration of GnRH agonist leads to down-regulation of GnRH receptors in the 
pituitary gland, which results in the complete suppression of luteinizing hormone (LH), 
follicle-stimulating hormone, and gonadal steroids after an initial stimulatory phase. Among 
currently available GnRH agonists, administration of leuprolide acetate has shown satisfactory 
efficacy with tolerable side-effects [9 ]. 
Leuprolide acetate is the synthetic analogue of naturally-occurring GnRH. Chemically modified on 
residues 6 and 10, leuprolide acetate possesses higher binding affinity to androgen receptors and is 
more stable than the naturally-occurring GnRH [10 ]. Within weeks of treatment, prostate cancer 
patients receiving leuprolide acetate showed significant suppression of serum testosterone level, 
similar to surgical castration. Treatment with a GnRH agonist is considered the standard of care for 
palliative therapy for prostate cancer patients. 
1.3. 
Study Rationale 
Leuprolide acetate (Lupron Depot®) was initially given by daily subcutaneous injections when it 
was first approved in 1985. Eligard® 22.5 mg (Sanofi-Aventis US, LLC) was a novel formulation 
incorporating leuprolide acetate with a biodegradable polymer matrix (Atrigel®  delivery system). It 
was designed to deliver 22.5 mg of leuprolide acetate at a controlled rate over a 3-month period of 
time. Thorough mixing of leuprolide acetate lyophilized powder and the co-polymer, poly (D, 


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L-lactide-co-glycolide) (PLGA) prior to subcutaneous injection was essential and critical for 
delivering a sufficient dose. Improvements in depot formulations enabled convenient subcutaneous 
or intramuscular injection of leuprolide given in the monthly basis. A variety of sustained-release 
formulations are now commercially available and some in development, including leuprolide 
mesylate. The current investigational product, LMIS 25 mg (Foresee Pharmaceuticals Co., Ltd), is 
the mesylate salt of leuprolide with biological activity comparable to Eligard® 22.5 mg. LMIS 25 
mg is designed to deliver 25 mg of leuprolide mesylate at a controlled rate over a 3-month period. 
The LMIS 25 mg formulation uses the same solvent,
 
However, a different polymer system, 
 is applied to allow 
sustained release of leuprolide. LMIS 25 mg successfully solved the stability issues of Eligard®. 
Thus, LMIS 25 mg is supplied as a single, sterile, pre-filled syringe. It is ready-to-use; no 
premixing is required prior to subcutaneous injection. 
Preclinical investigations with LMIS 25 mg have shown similar biological activity, 
pharmacokinetic, pharmacodynamic, and safety profiles, when compared to Eligard® 22.5 mg. A 
3-month depot leuprolide acetate formulation has been shown to possess similar clinical efficacy 
and side effect profiles to marketed depot formulations. The 3-month depot formulation is 
considered a convenient treatment option for patients with prostate cancer [11, 12, 13, 14, 15, 16, 17, 18]. A 
12-month, open-label, multicenter clinical trial showed that in patients with prostate cancer, 
6-month leuprolide acetate injections induced reliable and effective suppression of testosterone 
comparable to bilateral orchiectomy [17]. A recent large-scale study also has shown favorable 
results [9] with 6-month leuprolide acetate treatment. Notably, a lower dose of leuprolide acetate 
also showed efficacy in achieving castrate testosterone levels and with tolerable safety profile in 
Asian prostate cancer patients [19]. Thus, different dosage forms of leuprolide acetate have been 
developed. 
With regard to human use experience with leuprolide mesylate injectable suspension (LMIS) 
developed by Foresee, a recent Phase III study using LMIS 50 mg as a 6-month deport formulation 
in prostate cancer patients (study number FP01C-13-001) was conducted. The study design of 
FP01C-13-001 was in accordance with prior discussion with the FDA and was conducted in the 
USA, Europe, and Taiwan. Briefly, 137 subjects with prostate cancer were enrolled in the 
multi-national, multi-center, single-arm, open-label study. These subjects were treated with 2 
subcutaneous doses of LMIS 50 mg given 6 months apart. Primary endpoints included safety and 
tolerability assessments throughout 1 year of treatment; efficacy evaluation was based on the 
percentage of subjects with a serum testosterone concentration suppressed to castrate levels (≤ 50 
ng/dL) by Day 28 ± 1 day following the first injection of LMIS 50 mg and the percentage of 
subjects with serum testosterone suppression (≤ 50 ng/dL) from Day 28 through Day 336 
(remaining duration of the study). The assessment of PK profile of leuprolide mesylate was also 
included.  
In the Phase III study (study number FP01C-13-001), a total of 137 subjects were enrolled and 
received at least one dose of the study drug (ITT population), and 124 subjects completed the study 
without major protocol violations that would affect the primary efficacy endpoint (per-protocol 
population (PP)). The primary efficacy endpoint was achieved in 97.0% of subjects in both ITT 
and PP populations. The 95% confidence interval from Kaplan-Meier estimates was (92.2%, 
98.9%), and the 95% Repeated-Confidence Interval (RCI) was (92.5%, 99.4%). By Day 28, mean 
testosterone concentration was suppressed below the castrate level to 17.6 ng/dL, and the 


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suppression rate was 98.5% (135 out of 137 subjects achieved medical castration). No mean 
increase in testosterone was observed after the second injection. Four subjects did not have 
successful suppression of testosterone by the primary efficacy endpoint analysis, two of whom 
failed to achieve castration level on Day 28 and the other two had transient testosterone escapes.   
The secondary endpoints of this study were to determine the effect of LMIS 50 mg on (1) the 
proportion of subjects exhibiting post-suppression excursions of serum testosterone to > 50 ng/dL, 
either through “breakthrough” (i.e., episodes unrelated to LMIS 50 mg dosing), or through the 
“acute-on-chronic” surge (i.e., related to the second dose of LMIS 50 mg), (2) the effect of LMIS 
50 mg on serum PSA levels, (3) the effect of LMIS 50 mg on serum LH levels.   
In the FP01C-13-001 study, only two subjects exhibited post-suppression excursions. These 
post-suppression excursions occurred after the second dose of LMIS 50 mg injection on Day 168 
to Day 171. These effects were attributed to mild, transient acute-on-chronic surge. Serum 
testosterone levels in all the above subjects returned to below the castrate level shortly thereafter. 
No other breakthrough of serum testosterone to > 50 ng/dL was observed in this study.  
The administration of LMIS 50 mg significantly reduced the serum PSA levels from the first 
injection until the end of study in both ITT and PP populations. The mean serum PSA level was 
reduced by almost 85% and 89%, in ITT and PP populations, respectively, compared to the mean 
baseline level. The administration of LMIS 50 mg also significantly reduced the mean serum LH 
levels after the first injection and this effect remained until the end of study. The average serum LH 
level was significantly reduced by 98% by Day 336 in both ITT and PP populations.  
With regard to the safety of LMIS 50 mg in prostate cancer patients, of 137 subjects enrolled, the 
most common (≥5%) TEAEs observed by preferred term was hot flush (48.9%), followed by 
hypertension (14.6%), pain in extremity (9.5%), injection site pain (7.3%), arthralgia (6.6%), 
fatigue (6.6%), nocturia (5.8%), back pain (5.1%) and nasopharyngitis (5.1%). With regard to the 
severity of TEAEs, most TEAEs were mild or moderate. Of 137 enrolled subjects, 62% subjects 
(85/137) were reported with drug-related AEs determined by investigators. The most common 
(≥5%) drug-related AEs observed by preferred term was hot flush (48.2%), followed by injection 
site pain (7.3%) and fatigue (5.8%).  
There were 3 deaths reported (3/137, 2.2%) in this study. All three fatal events were determined to 
be unrelated to the use of LMIS 50 mg by investigator. Overall, the administration of LMIS 50 mg 
demonstrated a tolerable safety profile similar to that of Eligard® 45 mg. A 1-year (2 years total 
exposure) safety extension study of LMIS 50 mg in prostate cancer patients has been initiated and 
is currently ongoing to follow up on the safety profile of LMIS 50 mg (FP01C-13-001-EX). 
Foresee Pharmaceuticals is currently developing leuprolide mesylate 25 mg injectable suspension 
(LMIS 25 mg) as a line-extension product. Foresee expects that the subcutaneous injection of 
LMIS 25 mg will be equivalent or similar to the pharmacodynamic effects of the Eligard® 22.5 mg 
3-month depot formulation in subjects with prostate cancer. The current study is designed to 
determine the safety, tolerability, and efficacy of LMIS 25 mg for up to 24 weeks of exposure in 
subjects with prostate cancer. Moreover, the pharmacokinetic profile of serum leuprolide following 
2 separate subcutaneous injections of LMIS 25 mg will be evaluated. 
 


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2. 
STUDY OBJECTIVE AND ENDPOINTS 
LMIS 25 mg is supplied as a pre-mixed drug product containing 25 mg leuprolide mesylate (21 mg 
of leuprolide free base) formulated in 
o control and sustain the 
release of the bioactive leuprolide over a 3-month period following subcutaneous administration. 
The purpose of this study is to evaluate the safety, efficacy, and pharmacokinetic behavior of LMIS 
25 mg in subjects with prostate cancer after two subcutaneous depot injections given 12 weeks apart 
(on Day 0 and Day 84). 
2.1. 
Study Objective 
2.1.1. 
Primary objective 
• 
To assess the efficacy and safety of LMIS 25 mg for up to 24 weeks following 2 
subcutaneous doses given 12 weeks apart in subjects with prostate cancer 
2.1.2. 
Secondary objective 
• 
To establish the serum PK profile of leuprolide for LMIS 25 mg in a subset of 
subjects with prostate cancer 
 
2.2. 
Study Endpoints 
2.2.1. 
Primary endpoints 
The primary endpoints of efficacy are to determine: 
• 
The percentage of subjects with a serum testosterone concentration suppressed to 
castrate levels (≤ 50 ng/dL) on Day 28 ± 1 day (week 4) following the first injection 
of LMIS 25 mg, and the proportion of subjects with serum testosterone suppression 
(≤ 50 ng/dL) from Day 28 ± 1 day (week 4) through Day 168 ± 5 days (week 24) until 
the end of the study 
2.2.2. 
Secondary endpoints 
2.2.2.1  Efficacy:  
• 
The mean acute-on-chronic (surge) changes in testosterone and LH levels from just 
prior to the second injection through 14 days after the second injection of LMIS 25 
mg (Days 85-87, week 13; Day 98 [14 days post the second dose], week 14) 
• 
Effect of LMIS 25 mg on change of serum prostate-specific antigen (PSA) levels  
• 
Effect of LMIS 25 mg on change of serum LH levels  
• 
The percentage of subject with PSA relapse defined as after achieving the serum 
PSA level ≤ 4 ng/mL post LMIS 25 mg injection but with an increase in serum PSA 
of >50% PSA nadir by Day 168 (week 24) 


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• 
The percentage of subject achieving normal serum PSA level (<4 ng/dL) on Day 168 
± 5 days (week 24) 
• 
The percentage of subjects with enhanced serum testosterone concentration 
suppression to ≤ 20 ng/dL on Day 28 ± 1 day (week 4) and on Day 168 ± 5 days 
(week 24) 
2.2.2.2 Safety 
• 
Adverse event (AE)/ serious adverse event (SAE) reporting 
• 
Assessment of injection site reaction 
• 
Change in bone pain measurement (by Visual Analogue Scale [VAS] scale) 
• 
Change in urinary signs and symptoms and total scores (by the International 
Prostate Symptom Score, I-PSS sheet) 
• 
Change in vital signs (BP, HR, RR, weight) 
• 
Change in physical examinations with clinical significance compared to baseline by 
principal investigator’s judgment   
• 
Change in lab data, including liver function (AST, ALT, ALP), renal function 
(BUN, SCr), complete blood count with platelets, clinical chemistries (K, Na, Mg, 
Ca and P), urinalysis, serum glucose, lipid profile (LDL, HDL, triglycerides), and 
HbA1c level 
• 
Clinically significant changes in 12-lead resting electrocardiogram (ECG) per the 
investigator’s judgment 
2.2.2.3 Pharmacokinetic 
• 
The serum pharmacokinetic profile of leuprolide for up to 26 weeks following 2 
subcutaneous injections of LMIS 25 mg given 12 weeks apart will be determined 
from baseline to Day 168 (week 24) in a subset of subjects. This subset of subjects 
will be followed for an additional two weeks to week 26 (Day 182) after the second 
injection. 
The PK parameters of leuprolide will be determined during the study period, 
including Cmax, Tmax, Cweek4, Cweek12, AUC0-week4, AUC0-week12, Cavg (0-week12) after 
each dose. 
2.2.2.4 Exploratory: 
• 
The PK/PD analysis (serum testosterone and leuprolide levels) in the first enrolled 
30 subjects on Day 182 (week 26) 
The extended serum pharmacokinetic/pharmacodynamics profile of leuprolide and 
testosterone levels will be followed for additional 2 weeks post Day 168 in the first 
enrolled 30 subjects (PK subset). 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a multi-national, multi-center, open-label, single-arm study. All subjects will be males with 
prostate cancer judged to be candidates for medical androgen ablation therapy and all will receive 
LMIS 25 mg in an unblinded fashion. Subjects with morning serum testosterone level > 150 ng/dL 
at screening, adequate organ functions, ECOG performance score ≤ 2, and have a life expectancy of 
at least 18 months will be eligible to enter the study. 
The study duration is approximately 24 weeks. Two separate doses of LMIS 25 mg will be given to 
subjects by subcutaneous injection at 12 weeks apart in an unblinded manner. LMIS 25 mg will be 
administered on Day 0 (Visit 2) and Day 84 (Visit 13). At the end of 12 weeks (Day 84), all 
subjects who have tolerated LMIS 25 mg will be administered the second dose of LMIS 25 mg and 
will be followed for tolerability, safety, efficacy, PK/PD parameters for another 12 weeks (Day 
168/week 24).  
To evaluate the sustained castration testosterone level after two doses of LMIS 25 mg injections, the 
first enrolled 30 subjects are considered as a subset for PK assessment and will be followed for an 
additional 2 weeks (Day 182/week 26) post Day 168 (week 24) to establish the extended 
pharmacokinetic and pharmacodynamics profiles of serum leuprolide and testosterone levels. This 
additional sampling is meant to assess the flexibility of the time period between doses during 
routine use of LMIS 25 mg. 
The efficacy assessments will be performed in both ITT and PP populations. Efficacy assessment 
will include the percentage of subjects reached the castrate levels (≤ 50 ng/dL) of serum 
testosterone on Day 28 (week 4) post the first dosing of LMIS 25 mg, the effect of LMIS 25 mg on 
serum levels of testosterone, PSA, and luteinizing hormone (LH). The acute-on-chronic (surge) 
effect of serum testosterone and LH will also be monitored in all subjects. In addition, the effects of 
LMIS 25 mg on the percentage of subject with PSA relapse and on the percentage of subjects that 
achieves normal serum PSA level will be determined at the end of study. 
Safety assessments will include AE/SAE monitoring. All AEs and SAEs that occur during the study 
period will be recorded in Case Report Forms (CRFs) and followed until resolution or until the 
events are considered stable. In addition, SAEs will be recorded and reported as required by both 
local and international regulatory requirements.  
Additional safety assessments include vital signs, physical examinations, local injection site 
reaction, assessments of bone pain, urinary signs, and symptoms, and laboratory assessments.  
All concomitant medication used during the study period will be recorded in the CRF until the end 
of the study. 
Pharmacokinetic assessments of serum leuprolide levels will be performed using a validated liquid 
chromatography-tandem mass spectrometry (LC/MS/MS) method. To evaluate the sustained 
castration testosterone level after two doses of LMIS 25 mg injections, the first 30 subjects will 
have extended sampling time points to establish the full PK/PD profile of serum leuprolide by 
collecting blood samples on Day 0 (prior to the first dose of LMIS 25 mg, and at 2, 4, and 8 hours 
post-dose), Days 1, 2, 3, 7, 14, 21, 28, 42, 56, 77, 84 (week12: prior to the second dose and at 2, 4, 


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and 8 hours post the second dose), Days 85, 86, 87, 98, 112, 126, 140, 161, 168 (week 24) and 182 
(week 26, end of study (EOS)).  
The remaining approximately 103 subjects will have blood samples collected for determining the 
serum leuprolide on Day 0 (prior to the first dose of LMIS 25 mg, and 4 hours post the first dose), 
Days 1, 3, 14, 21, 28, 56, 77, 84 (week12: prior to the second dose and 4 hours post dose), 85, 86, 
87, 98, 112, 140, 161, and 168 (week 24/end of study (EOS)). 
The pharmacokinetic parameters of leuprolide will be determined during the study period using 
non-compartmental approaches with Phoenix WinNonlin®, including Cmax, Tmax, Cweek4, Cweek12, 
AUC0-week4, AUC0-week12, Cavg(0-12week) after each dose. The Day 182 (week 26) leuprolide serum 
concentration data from the first 30 subjects will also be determined. 
Serum testosterone and LH levels will be determined in all subjects using blood samples collected 
at the specified time points along with serum leuprolide analysis.  
Blood samples for determining the extended PK/PD profile of serum testosterone concentrations 
will be collected in the first enrolled 30 subjects on Day 0 (prior to the first dose of LMIS 25 mg 
and 2 h, 4 h, and 8 h post dose), Days 1, 2, 3, 7, 14, 21, 28, 42, 56, 77, 84 (week 12: prior to the 
second dose and 2 h, 4 h, and 8 h post dose), Days 85, 86, 87, 98, 112, 126, 140, 161, 168 (week 24) 
and Day 182 (week 26). 
For determining the serum testosterone concentration in the remaining 103 subjects, blood samples 
will be collected on Day 0 (prior to the first dose of LMIS 25 mg and 4 hours post dose), Days 1, 3, 
14, 21, 28, 56, 77, 84 (week 12: prior to the second dose of LMIS 25 mg and 4 hours post dose), 85, 
86, 87, 98, 112, 140, 161, and 168 (week 24/end of study (EOS)). 
Blood samples for determining the serum LH concentrations will be collected on Day 0 (prior to the 
first dose of LMIS 25 mg), Days 1, 2, 3, 7, 14, 21, 28, 42, 56, 77, 84 (week 12, prior to the second 
dose of LMIS 25 mg), 85, 86, 87, 98, 112, 126, 140, 161, 168 (week 24; end of study) in the first 
enrolled 30 subjects. 
For determining the serum LH concentration in the remaining 103 subjects, blood samples will be 
collected on Day 0 (prior to the first dose of LMIS 25 mg), Days 1, 3, 14, 21, 28, 56, 77, 84 (week 
12: prior to the second dose of LMIS 25 mg), 85, 86, 87, 98, 112, 140, 161, and 168 (week 24/end 
of study (EOS)). 
Serum testosterone concentrations will be measured using a validated LC/MS/MS method. The 
method validation follows the European Medicines Agency (EMA) Guideline on Bioanalytical 
Method Validation (EMEA/CHMP/EWP/192217/2009) and the FDA Guidance for Industry: 
Bioanalytical Method Validation, May 2001. 
The measurement of serum LH concentrations will be performed using validated, commercial assay 
kits at the BA lab.  
For subjects who terminate early or withdraw, phone contacts will be performed at 12 weeks after 
the last injection of the investigational product (IP) to collect information concerning drug-related 
AEs, concomitant medication, non-drug therapy received for AE treatment, disease progression 
status, and subject survival status. 
 


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4. 
ELECTION AND WITHDRAWAL OF SUBJECTS 
The criteria for enrollment must be adhered explicitly. 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study: 
1. Males aged ≥ 18 years old 
2. Males with histologically confirmed cancer of the prostate 
3. Subjects who are judged by the attending physician and/or principal investigator to be a 
candidate for androgen ablation therapy 
4. Baseline morning serum testosterone level > 150 ng/dL performed at screening visit 
5. Eastern Cooperative Oncology Group (ECOG) Performance score ≤ 2 
6. Life expectancy of at least 18 months 
7. Laboratory values 
 Absolute neutrophil count ≥ 1,500 cells/µL 
 Platelets ≥ 100,000 cells/µL 
 Hemoglobin ≥ 10 gm/dL 
 Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 
 AST (SGOT) ≤ 2.5 × ULN 
 ALT (SGPT) ≤ 2.5 × ULN 
 Serum creatinine ≤ 1.5 mg/dL 
 Lipid profile within acceptable range according to investigator’s opinion 
 Serum glucose within acceptable range according to investigator’s opinion 
 HbA1c ≤9.5% 
 Clinical chemistries (K, Na, Mg, Ca and P) within acceptable range according to 
investigator’s opinion 
 Normal urinalysis results within: 
 RBCs ≤ 3 RBCs/hpf 
 WBCs ≤ 5 WBCs/hpf   
 Nitrate: negative 
 Glucose: <0.1g/dL; but <1.0 g/dL in subjects with diabetes mellitus  
8. Agree to use male contraceptive methods during study trial 


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9. In the investigator’s opinion, the ability to understand the nature of the study and any hazards 
of participation, and to communicate satisfactorily with the investigator and to participate in, 
and to comply with, the requirements of the entire protocol 
10. All aspects of the protocol explained and written informed consent obtained 
4.2. 
Exclusion Criteria 
Subjects presenting with any of the following will not be included in the present study. 
1. Receipt of chemotherapy, immunotherapy, cryotherapy, radiotherapy, or anti-androgen 
therapy concomitantly, or within 8 weeks prior to screening visit, for treatment of Cancer of 
the prostate. Radiation for pain control will be allowed during the study. 
2. Receipt of any vaccination (including influenza) within 4 weeks of screening visit 
3. History of blood donation within 2 months of screening visit 
4. History of anaphylaxis to any LH-RH analogues 
5. Receipt of any LH-RH suppressive therapy within 6 months of screening visit 
6. Patients who were previously enrolled in the LMIS 50 mg study 
7. Major surgery, including any prostatic surgery, within 4 weeks of screening visit 
8. History and concomitant clinical and radiographic evidence of central nervous system/spinal 
cord metastases and subjects at risk for spinal cord compression  
9. Clinical evidence of active urinary tract obstruction and subjects at risk for urinary obstruction 
10. History of bilateral orchiectomy, adrenalectomy, or hypophysectomy 
11. History or presence of hypogonadism, or receipt of exogenous testosterone supplementation 
within 6 months of screening visit 
12. Clinically significant abnormal ECG and/or history of clinically significant cardiovascular 
disease as judged by the investigator 
13. History of drug and/or alcohol abuse within 6 months of screening visit 
14. Contraindication to leuprolide or an LH-RH agonist as indicated on package labeling 
15. Use of 5-alpha reductase inhibitor within the last 6 months of screening visit 
16. History or presence of insulin-dependent diabetes mellitus (Type I). Presence of well 
controlled diabetes mellitus Type II will be allowed if only oral hypoglycemic are required. 
Prostate cancer subjects with poor controlled diabetes mellitus with Hb1Ac > 9.5% or urine 
glycosuria > 1.0 g/dL should be excluded. 
17. Use of systemic corticosteroids at a dose > 10 mg/d or anti-androgens 
18. Use of any investigational agent within 4 weeks of screening visit 
19. Use of any over-the-counter (OTC) medication within 4 weeks of screening visit except for 
those listed in the permitted Concomitant Treatment section. 


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20. Uncontrolled intercurrent illness that would jeopardize the subject’s safety, interfere with the 
objectives of the protocol, or limit the subject’s compliance with study requirements, as 
determined by the investigator in consultation with the sponsor 
4.3. 
Withdrawal Criteria 
Discontinuation from study is defined as discontinuation of all study visits and examinations. 
Participants may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, or fail to return for visits, or become 
lost to follow up for any other reason. 
Subjects will be withdrawn from the study if any of the following occurs during the study period, 
i.e. from screening visit to the end of study (EOS): 
(1) Lost to follow-up  
(2) Subject withdrew consent 
(3) In investigator’s opinion that treatment with prohibited medications is needed  
(4) Adverse event/serious adverse event  
(5) Protocol violation (please provide specific reason) 
(6) Lack of efficacy as determined by investigator 
(7) Subjects with persistent, non-castrate serum testosterone levels (>50 ng/dL)  
(8) Other 
Subjects who are withdrawn due to AEs or SAEs will be followed until these events are resolved or 
until the event is considered stable.  
Should a subject’s testosterone concentration be above the castration level (> 50 ng/mL) at or after 
Visit 9 (Day 28/week 4), an extra visit for confirmation of testosterone level will be issued 
immediately. Subjects will be withdrawn from the study at the time of confirmation from the repeat 
testosterone analysis. The investigators can provide other alternative treatments promptly to these 
withdrawn subjects in accordance with standard clinical practice. 
 
 
 


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5. 
STUDY TREATMENT 
5.1. 
Treatment Plan Summary 
This is a multi-national, multi-center, Phase III, open-label, single dose study. All eligible 
subjects will receive two separate doses of LMIS 25 mg by subcutaneous injection with 12 weeks 
apart.  
LMIS 25 mg is a pre-mixed drug product containing 25 mg leuprolide mesylate (equivalent to 21 
mg of leuprolide free base) formulated in a suspension of NMP and PLGA to control and sustain 
the release of the bioactive leuprolide over a 3-month period after a single subcutaneous 
administration. It is intended to be used as the palliative treatment of prostatic cancer. 
Subjects with prostate cancer will be screened and enrolled into this study if eligible. After 
enrollment, subjects will receive the first dose of LMIS 25 mg by subcutaneous injection on Day 
0 and then receive the second dose of LMIS 25 mg on Day 84 (week 12 after the first dose). All 
subjects will be followed for at least another 12 weeks after the second dose administration.  
5.2. 
Treatment Assignment 
Subjects will be assigned a screening number after the subject signs the informed consent 
document. Only qualified subjects will be enrolled and uniquely identified by an enrolled number. 
The enrolled number should be recorded on the CRF. 
5.3. 
Description of Study Drug 
Leuprolide is a synthetic nonapeptide analog and agonist of the naturally occurring LH-RH or 
GnRH receptor. Leuprolide is a more potent agonist of the GnRH receptors relative to the natural 
GnRH peptide due to its increased affinity for the GnRH receptors and longer half-life. As a GnRH 
agonist, leuprolide functions as an inhibitor of gonadotropin secretion when administered 
continuously in therapeutic doses. Leuprolide acetate was introduced in 1985 for the treatment of 
prostate cancer as an alternative to surgical castration and estrogen therapy (NDA 19-010). Subjects 
with prostate cancer tend to accept this palliative treatment from a psychologic standpoint because it 
avoids surgical castration and also because its effects on gonadotropin are reversible when treatment 
is discontinued. 
Foresee Pharmaceuticals is developing LMIS 25 mg for the palliative treatment of prostate cancer. 
LMIS 25 mg is prefilled and supplied in a ready-to-use sterile syringe for subcutaneous injection 
and it is expected to deliver 25 mg leuprolide mesylate per syringe in a biodegradable poly 
(D,L-Lactide-co-Glycolide) (PLGA) polymer formulation dissolved in a biocompatible solvent, 
N-methyl-2-pyrrolidone (NMP). Investigational product dose administration procedures are 
outlined in the Investigational Product Instruction Manual. 
5.4. 
Rationale for Dose 
The LMIS 25 mg dosage form has been developed to deliver bioactive leuprolide over a 3-month 
period after subcutaneous administration with a controlled-release profile similar to that of the 


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Eligard® 22.5 mg formulation. The LMIS 25 mg dosage and its use as a sustained-release or depot 
dosage form have shown to be both efficacious and safe in similar leuprolide products (i.e., 
Eligard® 22.5 mg) as summarized in the Investigator Brochure. 
5.5. 
Warning and Precautions 
LMIS 25 mg contains the active pharmaceutical ingredient of leuprolide. Thus, the use of LMIS 25 
mg may cause adverse events similar to the established AE profiles observed in the use of leuprolide 
acetate. 
Leuprolide acetate has the following established significant AEs: 
 Transient clinical testosterone flare reaction in men with prostate cancer 
 Osteoporosis 
Like other LH-RH analogs, leuprolide acetate causes a transient increase in the serum concentration 
of testosterone during the first week of treatment. This effect may cause subjects to experience a 
worsening of symptoms or an onset of new symptoms including bone pain, neuropathy, hematuria, or 
ureteral or bladder outlet obstruction. Long-term use of an LH-RH agonist has been reported to 
decrease bone mineral density which can increase the risk of osteoporosis and skeletal bone fractures. 
Other reported adverse events of leuprolide acetate include hypogonadism, reduction in glucose 
tolerance, metabolic syndrome, anemia, and prolongation of the QT/QTc interval. 
5.6. 
Packaging and Labeling 
LMIS 25 mg will be provided to the investigator in a single use kit by Foresee Pharmaceuticals Co., 
Ltd, or its designee. A sterile syringe pre-filled with LMIS 25 mg suspension will be supplied with a 
standard, sterile 18 gauge needle, a plunger rod, and a backstop to facilitate subcutaneous injection. 
LMIS 25 mg pre-filled syringes are individually packaged in blisters which are placed in individual 
carton boxes. LMIS 25 mg kits are to be stored at 2 – 8C. 
Each site will be provided with emergency back-up kits of study drug in case of contamination or 
other loss. The investigational sites will be directed to assign specific emergency kits to individual 
subjects when needed by matching the subject’s code to the kit label. 
All investigational products are labeled with the information below; however, any additional 
information appearing on the label will conform to local regulatory requirements. 
 Product name 
 Batch number 
 Protocol number 
 Kit number 
 Storage instructions 
 Sponsor address 
 Use-by date 
 “Clinical trial use only” 


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The details noted on the labels are in accordance with applicable regulatory requirements. 
5.7. 
Supply, Delivery, Storage of Study Drug 
LMIS 25 mg (investigational product, IP) is supplied by Foresee Pharmaceuticals Co., Ltd. The IP 
will be shipped to the study site by a contracted delivery agent. The representative PI of the site will 
be in charge of the management and dispensation of the IP. Shipping receipts from receipt of IP or 
shipment of IP should be retained by the investigational site as part of the study records. 
LMIS 25 mg kits will be managed and stored at 2 – 8C, safely, and properly in a secured, lockable 
area by a designated, qualified person at the investigative site. 
5.8. 
Drug Dispensation and Accountability 
The investigational product will be administered to the subject by site staff designated by PI. The 
investigators and/or pharmacists must maintain records of the IP’s delivery to the study site, the IP 
inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition 
of unused IP. These records will include dates of administration, batch/serial numbers, used-by 
dates, and the subject (enrollment) number assigned to the study subject. At the time of return to the 
sponsor or alternative disposition, investigators must verify that all unused or partially used IP have 
been returned by the investigational sites and no remaining IP is in the investigators’ possession. 
The investigator or his/her delegate should complete the Study Treatment Record in the CRF. 
5.9. 
Treatment Exposure and Compliance 
All subjects will be administered LMIS 25 mg via subcutaneous injection at the study site. The 
administration of the IP to the subject will be under the supervision of the investigator and 
controlled by the clinical site personnel delegated to IP dispensing, preparation, and administration 
roles by PI. 
5.10. 
Treatment for Investigational Product Overdose 
The single-dose LMIS 25 mg will be carefully administered to each subject in two separate doses at 
12 weeks apart by investigators or professional clinical site personnel delegated by the investigator. 
If any accidental overdose injection is given, the subject should be closely monitored for safety and 
terminated from the study. 


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6. 
STUDY PROCEDURES 
This is a multi-national, multi-center, open-label, single-arm study. After providing a written 
informed consent, subjects with prostate cancer will be screened for baseline inclusion/exclusion 
criteria necessary for study eligibility. Eligible subjects will receive LMIS 25 mg from the prefilled 
syringes (without dilution or other mixing) in two separate subcutaneous injections given at 12 
weeks apart. 
Subjects who withdraw from the study prematurely for any reason during the study period will 
undergo the assessments listed for the final End of Study (EOS)/Early Termination (ET) visit. If a 
subject refuses to return for these assessments or is unable to do so, every effort should be made to 
contact him or a knowledgeable informant by telephone to determine his condition. Documentation 
of attempts to contact the subject should be recorded in the medical chart and CRF. 
After LMIS 25 mg administration, subjects will be evaluated. Blood and urine samples will be 
collected, and other procedures will be performed as shown in Tables 1a and 1b. The sign “X” 
indicates when the procedure should take place. 
 


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Table 1a 
Study Schedule Visits 1-13 
 
Scrn 
1st Dose 
Follow Up 
2nd Dose 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
 
1 
1 
1 
1 
1 
2 
3 
4 
6 
8 
11 
12 
12 
12 
12 
Day 
-28 to 
-1 
0 
1 
2 
3 
7 
14 
21 
28 
42# 
56 
77 
84* 
Hour 
 
0 
2 
4 
8 
 
 
 
 
 
 
 
 
 
 
0 
2 
4 
8 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject screening number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject enrollment number 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor history1/Medical and 
medication 
history2/comorbidity 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant treatments2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X 
X 
X 
Physical examination3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Vital signs4 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
 
 
 
ECOG PS 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG5 
X 
X 
 
X5 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X5 
 
Study treatment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Local injection site reaction  
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X  
X 
X 
Adverse event/SAE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X 
X 
X 
Hormone level 
Testosterone6 
X 
X 
X# 
X 
X# 
X 
X# 
X  
X# 
X 
X 
X 
X# 
X 
X 
X 
X# 
X 
X# 
Luteinizing hormone7 
X 
X 
 
 
 
X 
X# 
X  
X# 
X 
X 
X 
X# 
X 
X 
X 
 
 
 
Lab chemistry 


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Protocol No.: FP01C-17-001 
Version: 1.1  
Date: 24-Nov-2017 
41 
 
Scrn 
1st Dose 
Follow Up 
2nd Dose 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
 
1 
1 
1 
1 
1 
2 
3 
4 
6 
8 
11 
12 
12 
12 
12 
Day 
-28 to 
-1 
0 
1 
2 
3 
7 
14 
21 
28 
42# 
56 
77 
84* 
Hour 
 
0 
2 
4 
8 
 
 
 
 
 
 
 
 
 
 
0 
2 
4 
8 
Hematology8/ 
Biochemistry9 
X/X 
X/X 
 
 
 
 
 
 
 
X/X 
 
X/X 
 
 
 
X/X 
 
 
 
Pharmacokinetic 
serum 
sample 
for 
leuprolide 
mesylate (LM) 
 
X 
X# 
X 
X# 
X 
X# 
X 
X# 
X 
X 
X 
X# 
X 
X 
X 
X# 
X 
X# 
PSA 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Urinalysis10 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone pain (VAS)/ Urinary 
signs and symptoms (I-PSS) 
 
X/X 
 
 
 
X/X 
 
 
X/X 
X/X 
 
X/X 
 
X/X 
 
X/X 
 
 
 
Abbreviation: Baseline: Day 0; AE: Adverse Event; BT: Body temperature; ECG: Electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group Scale of 
Performance Status; EOS: end of study; ET: early termination; HbA1c: glycosylated hemoglobin; HR: Heart rate; LH: luteinizing hormone; PD: 
Pharmacodynamic(s); PK: Pharmacokinetic(s); PSA: Prostate Specific Antigen; RR: Respiratory rate; Scrn: Screening. BP: Blood pressure; VAS: Visual Analogue 
Scale; I-PSS International Prostate Symptom Score  
* If the subject cannot return on Day 84 (the second dose, Visit 13), please have the subsequent visits on Days 85, 86, 87, 98, and 112 to be scheduled 
according to the actual occurred date of the Day 84 visit. For the Day140 Visit (Visit 20), adjust the scheduled date according to the date when the 
first injection was received. 
# Procedures/ examinations for the first enrolled 30 subjects only. 
1 Cancer/tumor history should be recorded in a life-time basis. 
2 Medical and medication history (including procedural and surgical history, blood donations, and vaccinations) will be recorded up to 6 months 
prior to screening Visit. Concomitant medication use will be recorded up to 6 months prior to screening visit.  
3 Height will be only measured at screening visit. Weight will be measured at screening, Day 84, and EOS. 
4 Vital signs include BP, HR, RR, and BT. 
5 12-lead ECG monitoring will be performed at specified time points. When 12-lead ECG has to be performed on dosing days, it will be performed 
prior dosing and at 4-hour post LMIS 25 mg injection in all subjects on dosing days (Days 0 and Day 84). 


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Protocol No.: FP01C-17-001 
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Date: 24-Nov-2017 
42 
6 Testosterone samples will be collected in the morning at specified time points as shown in the above schedule. On dosing days (Day 0 and Day 
84), blood samples for testosterone analysis will be collected before LMIS 25 mg administration. Serum testosterone levels will be analyzed at 
the QPS Bioanalytical Lab. For fast turn-around of assay results, a sample for the screening testosterone will also be sent to the Central Lab. After 
that, additional samples for testosterone may be ordered by the investigator at their discretion and analyzed at the Central Lab using commercial 
diagnostic assays for fast turn-around of results. 
7 LH samples will be collected in the morning at specified time points as shown in the above schedule. On dosing days (Day 0 and Day 84), blood 
samples for LH analysis will be collected before LMIS 25 mg administration. Serum samples for LH concentrations will be analyzed at the BA lab 
using a validated ELISA method. More frequent tests of LH may be ordered by the investigators at their discretion, and these samples can be 
analyzed at the Central Lab for a faster data turn-around. Serum samples to the BA Lab will be batched and shipped periodically. 
8 Hematology tests include CBC, Hb, Hct, RBC count, WBC count with differential and platelet count. 
9 Biochemistry tests include ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, Mg, Ca and P), blood glucose, and lipid profile 
(LDL, HDL, triglycerides) 
10 Urinalysis tests include pH, specific gravity, leukocyte, erythrocyte, urine glucose, nitrate, and protein. 
Note: Regarding the time window for blood sample collection, at 2, 4, 8 hours post LMIS 25 mg administration on Day 0 (Visit 1) and 
Day 84 (Visit 13), a 15-minute time window is allowed; at Visits 6 to 9 (Day 7 to Day 28), a ± 1-day window is allowed. At Visits 10 
and 12 (Day 42 to Day 77), a ± 3-day window is allowed. At Visits 13 to 16 (Day 84, for the second dose injection, week 12, to Day 
87), only ± 1-day window is allowed. At Visits 17 to 21 (Day 98 to Day 161), a ± 3-day window is allowed. At Visits 22 (Day 168), a ± 
5-day window is allowed. At Visit 23 (Day 182), a ± 3-day window is allowed. 
 


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Protocol No.: FP01C-17-001 
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Table 1b 
Study Schedule Visits 14-EOS 
 
Follow Up 
EOS/ET PK-extended 
Follow up 
Visit 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23# 
Week 
13 
13 
13 
14 
16 
18 
20 
23 
24 
26 
Day 
85* 
86* 
87* 
98* 
112* 
126# 
140 
161 
168 
182# 
Concomitant treatments2 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X# 
Physical examination3 
 
 
 
 
 
 
 
 
X 
 
Vital signs4 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X# 
ECOG PS 
 
 
 
 
 
 
 
 
 
 
12-lead ECG5 
 
 
 
 
 
 
 
 
X 
 
Study treatment 
 
 
 
 
 
 
 
 
 
 
Local injection site reaction 
X 
X 
 
 
 
 
 
 
 
 
Adverse event/SAE 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X# 
Hormone level 
Testosterone6 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X# 
Luteinizing hormone7 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
 
Lab chemistry 
Hematology8/ Biochemistry9 
 
 
 
 
 
 
 
 
X/X 
 
Pharmacokinetic serum sample for 
leuprolide mesylate (LM) 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X# 
PSA 
 
 
 
 
 
 
 
 
X 
 
Urinalysis10 
 
 
 
 
 
 
 
 
X 
 
HbA1c 
 
 
 
 
 
 
 
 
X 
 
Bone pain (VAS)/ Urinary signs 
and symptoms (I-PSS) 
 
 
 
 
X/X 
 
X/X 
 
X/X 
 
Abbreviation: Baseline: Day 0; AE: Adverse Event; BT: Body temperature; ECG: Electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group Scale of 
Performance Status; EOS: end of study; ET: early termination; HbA1c: glycosylated hemoglobin; HR: Heart rate; LH: luteinizing hormone; PD: 
Pharmacodynamic(s); PK: Pharmacokinetic(s); PSA: Prostate Specific Antigen; RR: Respiratory rate; Scrn: Screening. BP: Blood pressure; VAS: Visual Analogue 
Scale; I-PSS: International Prostate Symptom Score. 


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* If the subject cannot return on Day 84 (the second dose, Visit 13), please have the subsequent visits on Days 85, 86, 87, 98, and 112 to be postponed 
according to the actual occurred date of the Day 84 visit. For the Day140 Visit (Visit 20), adjust the scheduled date according to the date when the first 
injection was received. 
# Procedures/ examinations for the first enrolled 30 subjects only. 
 For early termination subjects (ET), end of study (EOS) procedure and examination should be performed on that day. In addition, phone contacts 
should be performed at 12 weeks after the last injection of investigational product to collect drug-related AE, concomitant medication or non-drug 
therapy received for AE treatment, disease progression status, and subject survival status. 
2 Concomitant medication use will be recorded up to 6 months prior to screening visit. 
3 Height will be only measured at screening visit. Weight will be measured at screening, Day 84 (week 12), and EOS (Week 24). 
4 Vital signs include BP, HR, RR, and BT 
5 12-lead ECG monitoring will be performed at specified time points. 
6 
.Testosterone samples will be collected in the morning at specified time points as shown in the above schedule. Serum testosterone levels will be 
analyzed at the QPS Bioanalytical Lab.  
7 LH samples will be collected in the morning at specified time points as shown in the above schedule. On dosing days (Day 0 and Day 84), blood 
samples for LH analysis will be collected before LMIS 25 mg administration. Serum samples for LH concentrations will be analyzed at the BA lab 
using a validated ELISA method. More frequent tests of LH may be ordered by the investigators at their discretion, and these samples can be 
analyzed at the Central Lab for a faster data turn-around. Serum samples to the BA Lab will be batched and shipped periodically. 
8 Hematology tests include CBC, Hb, Hct, RBC count, WBC count with differential and platelet count. 
9 Biochemistry tests include ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, Mg, Ca and P), blood glucose, and lipid profile 
(LDL, HDL, triglycerides) 
10 Urinalysis tests include pH, specific gravity, leukocyte, erythrocyte, protein, urine glucose, and nitrate. 
Note: Regarding the time window for blood sample collection, at 2, 4, 8 hours post LMIS 25 mg administration on Day 0 (Visit 1) and 
Day 84 (Visit 13), 15-minute time window is allowed; at Visits 6 to 9 (Day 7 to Day 28), a ± 1-day window is allowed. At Visits 10 
and 12 (Day 42 to Day 77; week 6 to week 11), a ± 3-day window is allowed. At Visits 13 to 16 (Day 84 for the second dose injection, 
week 12 visit, to Day 87), only ± 1-day window is allowed. At Visits 17 to 21 (Day 98 to Day 161), a ± 3-day window is allowed. At 
Visits 22 (Day 168), a ± 5-day window is allowed. At Visit 23 (Day 182), a ± 3-day window is allowed. 


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6.1. 
Screening Visit 1 (Day -28 ~ -1) 
At the screening visit, informed consent must be obtained from the subject prior to performing any 
procedures related to the study and after the subject has received sufficient information about the 
study. 
Subjects who have been screened should be listed in the screening log at study sites. Moreover, all 
screening procedures conducted must be documented in the CRF. If the subject fails screening or 
decides not to continue in the study, the primary reason should be documented in the CRF. No data 
will be entered into the database for screened subjects who do not meet criteria for entering the 
study or decide not to continue in the study. No CRF sections other than the screening section will 
be completed for these subjects. 
Inclusion/exclusion criteria should be checked during this visit. The following study procedures 
will be conducted for screening assessments. 
1. Record date that informed consent is signed. The following should be documented in the 
subject’s medical chart: that they are participating in this study and informed consent has 
been obtained, and that a copy of the consent has been given to the subject. 
2. Assign subject screening number 
3. Collect demographic data 
4. Record tumor history (life-time basis), medical history and medication history (record up to 
6 months prior to screening visit; including blood donations and vaccinations) 
5. Conduct a complete physical examination, including the measurement of body height and 
weight. Measure and record the vital signs including the measurement of blood pressure, 
heart rate, respiratory rate, and body temperature. 
6. Perform Eastern Cooperative Oncology Group Performance Scale (ECOG PS) assessment 
7. Perform ECG 
8. Collect blood sample for analyses of: 
 Hormone: testosterone, luteinizing hormone 
 Hematology: CBC, including Hb, Hct, RBC count, WBC count, WBC differential and 
platelet count 
 Biochemistry: ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, 
Mg, Ca and P), blood glucose, lipid profile (LDL, HDL, triglycerides) 
 PSA level 
 Glycosylated hemoglobin (HbA1c) 
9. Collect urine sample for urinalysis  
 pH, specific gravity, leukocyte, erythrocyte, urine glucose, nitrate, and protein 
10. Serum samples for testosterone and LH will be sent to the BA lab and Central Lab for 
analyses.  
11. Record AE(s) if any 


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6.2. 
Visit 2 (Day 0; 1st Dose Administration) 
The following study procedures will be performed at this visit: 
1. Assign subject enrollment number prior to dosing. 
2. Record vital signs prior to dosing. 
3. Record the ECOG PS prior to dosing. 
4. Perform ECG prior to dosing and at 4-hour post-dosing. 
5. Collect blood sample prior to dosing for the analysis of: 
 Hematology: CBC, including Hb, Hct, RBC count, WBC count, WBC differential and 
platelet count 
 Biochemistry: ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, 
Mg, Ca and P), blood glucose, lipid profile (LDL, HDL, triglycerides) 
 PSA level 
6. Collect urine sample prior to dosing for urinalysis: pH, specific gravity, leukocyte, 
erythrocyte, urine glucose, nitrate, and protein. 
7. Collect serum samples for determining pharmacokinetics of leuprolide mesylate and 
testosterone levels at pre-dose and at 2, 4, and 8 hours post-dose in the first enrolled 30 
subjects. Collect serum samples at pre-dose and at 4 hours post-dose in the remaining 103 
subjects for testosterone and pharmacokinetic analysis of leuprolide. 
8. Collect serum samples for LH prior to dosing. 
9. Assess bone pain prior to dosing. 
10. Assess urinary signs and symptoms prior to dosing. 
11. Record concomitant medication(s) prior to dosing and post dosing. 
12. Record AE(s) prior to dosing and post dosing. 
13. Administer LMIS 25 mg. 
14. Investigator to assess local injection site reaction post dosing. 
6.3. 
Visit 3 (Day 1) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Investigator to assess local injection site reaction. 
3. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
4. Collect serum samples for testosterone and LH. 
5. Assess bone pain. 
6. Assess urinary signs and symptoms. 
7. Record concomitant medication(s). 


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8. Record AE(s). 
6.4. 
Visit 4 (Day 2) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Investigator to assess local injection site reaction. 
3. Collect serum samples for pharmacokinetics of leuprolide mesylate (from the first enrolled 
30 subjects only). 
4. Collect serum samples for testosterone and LH (from the first enrolled 30 subjects only).  
5. Record concomitant medication(s). 
6. Record AE(s). 
6.5. 
Visit 5 (Day 3) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone and LH. 
4. Record concomitant medication(s). 
5. Record AE(s). 
6.6. 
Visit 6 (Day 7 ± 1 day, week 1) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate (from the first enrolled 
30 subjects only). 
3. Collect serum samples for testosterone and LH (from the first enrolled 30 subjects only). 
4. Assess bone pain. 
5. Assess urinary signs and symptoms. 
6. Record concomitant medication(s). 
7. Record AE(s). 
6.7. 
Visit 7 (Day 14 ± 1 day, week 2) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Hematology: CBC, including Hb, Hct, RBC count, WBC count, WBC differential and 
platelet count. 


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3. Biochemistry: ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, Mg, Ca, 
and P), blood glucose, and lipid profile (LDL, HDL, triglycerides). 
4. Collect urine sample for urinalysis test: pH, specific gravity, leukocyte, erythrocyte, urine 
glucose, nitrate, and protein. 
5. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
6. Collect serum samples for testosterone and LH. 
7. Assess bone pain. 
8. Assess urinary signs and symptoms. 
9. Record concomitant medication(s). 
10. Record AE(s). 
6.8. 
Visit 8 (Day 21 ± 1 day, week 3) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone and LH. 
4. Record concomitant medication(s). 
5. Record AE(s). 
6.9. 
Visit 9 (Day 28 ± 1 day, week 4) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Perform ECG. 
3. Collect blood sample for analysis of: 
 Hematology: CBC, including Hb, Hct, RBC count, WBC count, WBC differential and 
platelet count 
 Biochemistry: ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, 
Mg, Ca and P), blood glucose, lipid profile (LDL, HDL, triglycerides) 
 PSA level 
4. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
5. Collect serum samples for testosterone and LH. 
6. Collect urine sample for urinalysis test: 
 pH, specific gravity, leukocyte, erythrocyte, urine glucose, nitrate, and protein 
7. Assess bone pain. 
8. Assess urinary signs and symptoms. 


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9. Record concomitant medication(s). 
10. Record AE(s). 
6.10. 
Visit 10 (Day 42 ± 3 days, week 6-for the first enrolled 30 subjects only)  
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate.  
3. Collect serum samples for testosterone and LH.  
4. Record concomitant medication(s). 
5. Record AE(s). 
6.11. 
Visit 11 (Day 56 ± 3 days, week 8) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone and LH. 
4. Assess bone pain. 
5. Assess urinary signs and symptoms. 
6. Record concomitant medication(s). 
7. Record AE(s). 
6.12. 
Visit 12 (Day 77 ± 3 days, week 11) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone and LH. 
4. Record concomitant medication(s). 
5. Record AE(s). 
6.13. 
Visit 13 (Day 84 ± 1 day; 2nd Dose Administration; week 12) 
The following procedures and sample collection should be performed at this visit: 
1. Conduct physical examination and record vital signs (including body weight) prior to dosing. 
2. Perform ECG prior to dosing and at 4-hour post-dosing. 
3. Collect blood sample prior to dosing for analysis of: 


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 Hematology: CBC, including Hb, Hct, RBC count, WBC count, WBC differential and 
platelet count 
 Biochemistry: ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, 
Mg, Ca, and P), blood glucose, lipid profile (LDL, HDL, triglycerides) 
 PSA level 
 Collect urine sample prior to dosing for urinalysis: pH, specific gravity, leukocyte, 
erythrocyte, protein, urine glucose, and nitrate. 
4. Collect serum samples for pharmacokinetic analysis of leuprolide mesylate and testosterone 
prior to dosing and at 2, 4, and 8 hours post-dosing in the first enrolled 30 subjects. Collect 
serum samples prior to dosing and at 4 hours post-dosing in the remaining 103 subjects for 
pharmacokinetic analysis of leuprolide mesylate and testosterone. 
5. Collect serum samples for LH prior to dosing. 
6. Assess bone pain prior to dosing. 
7. Assess urinary signs and symptoms prior to dosing. 
8. Record concomitant medication(s) prior to dosing and post dosing. 
9. Record AE(s) prior to dosing and post dosing. 
10. Administer LMIS 25 mg (second administration). 
11. Investigator to assess local injection site reaction post dosing. 
6.14. 
Visit 14 (Day 85 ± 1 day, week 13) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone and LH. 
4. Investigator to assess local injection site reaction.  
5. Record concomitant medication(s). 
6. Record AE(s). 
6.15. 
Visit 15 (Day 86 ± 1 day; week 13) 
The following procedures and sample collection should be performed at this visit  
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate.  
3. Collect serum samples for testosterone and LH.  
4. Investigator to assess local injection site reaction.  
5. Record concomitant medication(s). 


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6. Record AE(s). 
6.16. 
Visit 16 (Day 87 ± 1 day; week 13) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone and LH. 
4. Record concomitant medication(s). 
5. Record AE(s). 
6.17. 
Visit 17 (Day 98 ± 3 days, week 14) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone and LH. 
4. Record concomitant medication(s). 
5. Record AE(s). 
6.18. 
Visit 18 (Day 112 ± 3 days, week 16) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone and LH. 
4. Assess bone pain. 
5. Assess urinary signs and symptoms. 
6. Record concomitant medication(s). 
7. Record AE(s). 
6.19. 
Visit 19 (Day 126 ± 3 days; week 18 for the first enrolled 30 subjects 
only) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone and LH. 
4. Record concomitant medication(s). 


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5. Record AE(s). 
6.20. 
Visit 20 (Day 140 ± 3 days; week 20) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone and LH. 
4. Assess bone pain. 
5. Assess urinary signs and symptoms. 
6. Record concomitant medication(s). 
7. Record AE(s). 
6.21. 
Visit 21 (Day 161 ± 3 days, week 23) 
The following procedures and sample collection should be performed at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone and LH. 
4. Record concomitant medication(s). 
5. Record AE(s). 
6.22. 
Visit 22 (Day 168 ± 5 days/EOS/ ET; week 24) 
The following procedures and sample collection should be performed at this visit: 
1. Conduct physical examination (including body weight) and record vital signs. 
2. Perform ECG. 
3. Collect blood sample for analysis of the following: 
 Hematology: CBC, such as Hb, Hct, RBC count, WBC count, WBC differential and 
platelet count 
 Biochemistry: ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, 
Mg, Ca and P), blood glucose, lipid profile (LDL, HDL, triglycerides) 
 HbA1c 
 PSA level 
4. Collect urine sample for urinalysis: 
 pH, specific gravity, leukocyte, erythrocyte, protein, urine glucose, and nitrate 
5. Collect serum sample for pharmacokinetics of leuprolide mesylate. 
6. Collect serum samples for testosterone and LH. 


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7. Assess bone pain. 
8. Assess urinary signs and symptoms. 
9. Record concomitant medication(s). 
10. Record AE(s). 
11. Exit off the study (for the 103 subjects without extended PK follow up). 
12. For early termination subjects, phone contacts should be performed at 12 weeks after the last 
injection of investigational product to collect drug-related AE, concomitant medication or 
non-drug therapy received for AE treatment, disease progression status, and subject survival 
status. 
Subjects who withdraw from the study prematurely for any reason during the study period will 
undergo the assessments listed for the final End of Study (EOS)/Early Termination (ET) visit. If a 
subject refuses to return for these assessments or is unable to do so, every effort should be made to 
contact him or a knowledgeable informant by telephone to determine his condition. Documentation 
of attempts to contact the subject should be recorded in the medical chart and CRF. 
6.23. 
Visit 23 (Day 182 ± 3 days/PK-extended follow up; week 26) 
The following procedures and sample collection should be performed in the first enrolled 30 
subjects only at this visit: 
1. Record vital signs. 
2. Collect serum samples for pharmacokinetics of leuprolide mesylate. 
3. Collect serum samples for testosterone.  
4. Record concomitant medication(s). 
5. Record AE(s). 
6. Exit off the study (for the first enrolled 30 subjects only). 
 


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7. 
STUDY ASSESSMENTS 
7.1. 
Screening Assessment 
7.1.1. 
Informed consent form 
The investigator or designee must explain to each subject the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved and any 
potential AEs. Each subject will be informed that participation in the study is voluntary and that 
he can withdraw from participation at any time. 
All subjects must provide a signed and dated informed consent at the screening visit prior to 
dosing LMIS 25 mg. An informed consent form approved by the Institutional Review Board 
(IRB), Ethics Committee (EC), and/or the applicable health authorities must be used. 
7.1.2. 
Demographics / history 
The demographic and baseline characteristics data for all subjects will be collected at the 
screening visit. The demographics will include date of birth, age, gender, and ethnicity. 
The general medical history (including procedural and surgical history, blood donations, and 
vaccinations) from up to 6 months before the screening visit should be recorded at the CRF. 
Cancer history should be recorded in a life-time basis. 
1. Tumor history should be documented, including: 
 first diagnosis date, 
 histological evidence, 
 TNM classification 
 Staging 
 date of the last relapse or progression (if applicable) 
 previous treatment of malignant disease 
 Surgery 
 Radiation therapy 
 Chemotherapy/immunotherapy 
 Cryotherapy 
 Anti-androgen therapy 
 Other modalities 
Whenever possible, diagnoses should be recorded instead of symptoms. 


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7.1.3. 
Eligibility 
Eligibility should be thoroughly checked by the investigator at the screening visit. See Section 
4.1 and Section 4.2, Inclusion and exclusion Criteria for details. 
7.1.4. 
ECOG performance status 
ECOG performance status should be checked at the screening visit and on Day 0. The 
description of the ECOG performance status scale is as follows: 
0: 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1: 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work). 
2: 
In bed < 50% of the time. 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: 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4: 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5: 
Dead 
7.2. 
Efficacy Assessment 
Efficacy assessments will be performed based on the study schedule (Table 1a and 1b). The 
primary endpoint of efficacy is to determine the percentage of subjects with a serum testosterone 
concentration suppressed to castrate levels (≤ 50 ng/dL) on Day 28 ± 1 day (week 4) following the 
first injection of LMIS 25 mg, and the proportion of subjects with serum testosterone suppression 
(≤ 50 ng/dL) from Day 28 ± 1 day (week 4) through Day 168 ± 5 days (week 24) until the end of 
the study.  
The proportion of subjects exhibiting post-suppression breakthrough of serum testosterone to > 
50 ng/dL from Day 28 ± 1 day (week 4) through Day 168 ± 5 days (week 24) until the end of the 
study will also be determined. 
The secondary endpoints will determine the mean acute-on-chronic changes in serum 
testosterone level before injection of the second dose LMIS 25 mg on Day 84 (week 12) and on 
Days 85, 86, 87 (week 13), and 98 (2 weeks post the second injection). The percentage of 
subjects observed with acute-on-chronic (surge) effect on serum testosterone and LH levels just 
before the second dose administration and on Day 1 to Day 3 (Days 85, 86, 87) and 14 days (Day 
98) post the second injection of LMIS 25 mg will be analyzed.  
The effect of LMIS 25 mg on serum LH levels and the percentage of subjects with enhanced 
serum testosterone concentration suppression to ≤ 20 ng/dL on Day 28 ± 1 day (week 4) and on 
Day 168 ± 5 days (week 24) by LMIS 25 mg administration will also be determined. In addition, 
the effects of LMIS 25 mg on the percentage of subject with PSA relapse and the percentage of 
subjects that achieves normal serum PSA level will be determined at the end of study. 


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7.2.1. 
Hormone level 
Serum testosterone will be examined at the screening visit for eligibility (> 150 ng/dL). The 
screening sample of testosterone for eligibility will be sent to the Central Lab for analysis using a 
validated commercial assay. Thereafter, the serum testosterone can be sent to the Central Lab for 
analysis at the investigator’s discretion. The serum testosterone will also be measured at baseline 
(Day 0) and at each visit for analysis at the Bioanalytical Lab. Blood samples will be collected 
from approximately 133 subjects in the study.  
After enrollment, serum testosterone concentration in all subjects will be determined at baseline 
(Day 0) and at specified time points and will be sent for analysis at the Bioanalytical Lab. Blood 
samples for serum testosterone concentration measurement will be collected from all 133 
subjects in the present study. 
Serum testosterone concentrations will be measured by a validated LC/MS/MS method. The 
method validation follows the European Medicines Agency (EMA) Guideline on Bioanalytical 
Method Validation (EMEA/CHMP/EWP/192217/2009) and the FDA Guidance for Industry: 
Bioanalytical Method Validation, May 2001.  
For a faster sample turn-around, additional serum testosterone samples can also be analyzed by a 
validated, commercial diagnostic method. Additional testosterone tests (by a commercial method) 
will be ordered at a routine frequency of no more than monthly, which is consistent with 
standard medical practice for leuprolide therapy for the purpose of safety monitoring. More 
frequent tests may be ordered by the investigators at their discretion. 
Serum samples for LH concentrations will be analyzed at the BA lab using a validated ELSIA 
method. More frequent tests of LH may be ordered by the investigators at their discretion, and 
these samples can be analyzed at the Central Lab for a faster data turn-around. 
To establish the extended serum PK/PD relationship between leuprolide and testosterone levels, 
blood samples for determining the serum testosterone concentrations will be collected in the first 
enrolled 30 subjects on Day 0 (prior to the first dose of LMIS 25 mg and 2 h, 4 h, and 8 h post 
dose), Days 1, 2, 3, 7, 14, 21, 28, 42, 56, 77, 84 (week 12: prior to the second dose and 2 h, 4 h, 
and 8 h post dose), Days 85, 86, 87, 98, 112, 126, 140, 161, 168 (week 24) and Day 182 (week 
26). 
For determining the serum testosterone concentration in the remaining 103 subjects, blood 
samples will be collected on Day 0 (prior to the first dose of LMIS 25 mg and 4 hours post dose), 
Days 1, 3, 14, 21, 28, 56, 77, 84 (week 12: prior to the second dose of LMIS 25 mg and 4 hours 
post dose), 85, 86, 87, 98, 112, 140, 161, and 168 (week 24/end of study (EOS)). 
Blood samples for determining the serum LH concentrations will be collected on Day 0 (prior to 
the first dose of LMIS 25 mg), Days 1, 2, 3, 7, 14, 21, 28, 42, 56, 77, 84 (week 12, prior to the 
second dose of LMIS 25 mg), 85, 86, 87, 98, 112, 126, 140, 161, 168 (week 24; end of study) in 
the first enrolled 30 subjects. 
For determining the serum LH concentration in the remaining 103 subjects, blood samples will 
be collected on Day 0 (prior to the first dose of LMIS 25 mg), Days 1, 3, 14, 21, 28, 56, 77, 84 
(week 12: prior to the second dose of LMIS 25 mg), 85, 86, 87, 98, 112, 140, 161, and 168 (week 
24/end of study (EOS/ET)). 


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Serum samples to the BA Lab will be batched and shipped periodically. Detailed procedures for 
blood sample collection, processing, and analysis are provided in the Laboratory Manual. 
7.2.2. 
PSA level 
The PSA tumor marker will be assessed at specified visit as one of the endpoint assessments in 
all subjects. Blood samples will be collected at the screening visit, Day 0 (prior to dosing), Day 
28 ± 1 day (week 4), Day 84 ± 1 (prior to dosing, week 12), and Day 168 ± 5 days (week 24, 
EOS/ET). All collected blood samples will be sent to the central laboratory for analysis. More 
frequent tests may be ordered by the investigators at their discretion. 
Detailed procedures for blood sample collection, processing, and analysis are provided in the 
Laboratory Manual. 
7.3. 
Safety Assessment 
7.3.1. 
Physical examinations and vital signs 
Physical examination will be performed in all subjects at the screening visit, Day 84 ± 1 day 
(week 12), and Day 168 ± 5 days (week 24, EOS/ET), by standard physical examination 
including general appearance, skin, eyes, ear/nose/throat (ENT), head and neck, heart, chest and 
lungs, abdomen, extremities, lymph nodes, musculoskeletal, neurological, and other body 
systems if applicable for describing the status of the subject’s health. 
Changed in physical examinations with clinical significance compared to baseline by principal 
investigator’s judgment will be analyzed. 
Height in centimeters (cm) will be measured while the subject is standing after removing his 
shoes, and the measurement will only be conducted at screening visit. Body weight will be 
measured at the screening visit, Day 84 (week 12), and Day 168 ± 5 (week 24, EOS/ET) to the 
nearest 0.1 kilogram (kg) or pound (lb.) in indoor clothing without shoes. 
Vital signs will be measured at each visit, including resting blood pressures, heart rate, 
respiratory rate, and body temperature. 
7.3.2. 
Local injection site reaction assessment 
The specific injection location chosen should be an area with sufficient soft or loose 
subcutaneous tissue, for example, the upper- or mid-abdominal area. Local AEs have been 
reported in Eligard® studies. The local AEs typically seen with subcutaneously injected products 
include: transient burning, stinging, and pruritus at the injection site and are typically of mild 
intensity and brief duration. 
The local injection site reaction assessments should include itchiness, erythema, burning and 
stinging sensation. Assessments will be carried out after investigational product administration 
and recorded on Day 0, Day 1, Day 2, Day 84, Day 85, and Day 86.  
Any local site injection reactions will be captured under AE reporting at the next follow up visit 
if last longer than 3 days with any severity post LMIS 25 mg administration. The grading for the 
assessment of local injection reaction is provided in Table 2. 
 
 


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Table 2 
Grading of local injection reaction 
 
Grade 
Burning/Stinging 
Pruritus 
Erythema 
0 
(None) 
No stinging / burning 
No pruritus  
No detectable 
erythema, skin of 
normal color 
1 
(Mild) 
Slight warm, tingling 
sensation; not really 
bothersome 
Occasional, slight 
itching / scratching  
Slight pinkness 
present  
2 
(Moderate) 
Definite warm, tingling 
sensation that is 
somewhat bothersome 
Constant or 
intermittent 
itching / scratching 
which is not disturbing 
sleep  
Definite redness, 
easily recognized 
 
 
3 
(Severe) 
Hot, tingling / stinging 
sensation that has caused 
definite discomfort 
Bothersome itching 
/scratching which is 
disturbing sleep  
Intense redness 
 
7.3.3. 
Hematological / biochemistry examinations 
The safety profile of LMIS 25 mg will be assessed using lab test including hematological and 
biological examinations by collecting blood samples from all subjects. 
Hematological tests will include complete blood count (CBC): hemoglobin (Hb), hematocrit 
(Hct), red blood cells (RBC), white blood cells (WBC), WBC differential (neutrophils, 
eosinophils, basophils, lymphocytes, and monocytes), platelet counts, and HbA1c. Biochemistry 
tests will include ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, Mg, Ca 
and P), blood glucose and lipid profile (LDL, HDL, triglycerides). 
Laboratory tests, except for the HbA1c, will be performed during the screening visit and on Day 
0 (prior to dosing), Day 14 ± 1 day (week 2), Day 28 ± 1 day (week 4), Day 84 ± 1 (prior to 
dosing, week 12), and Day 168 ± 5 days (week 24, EOS/ET).  
The HbA1c will be performed at the screening visit and at the final visit (Day 168, week 24, or 
End of Study Visit/Early termination).  
Blood samples for laboratory tests will be collected and will be sent to the Central Laboratory for 
analyses. 


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7.3.4. 
Urinalysis 
Urinalysis will be collected from all subjects to assess the safety profile of LMIS 25 mg. The 
urinalyses will include urine pH, specific gravity, leukocyte, erythrocyte, urine glucose, nitrate, 
and protein. 
The urinalysis will be performed at screening, Day 0 (prior to dosing), Day 14 ± 1 day (week 2), 
Day 28 ± 1 day (week 4), Day 84 ± 1 (prior to dosing, week 12), and Day 168 ± 5 days (week 24, 
EOS/ET). 
Urine samples will be collected and sent to the Central Laboratory for analyses. 
7.3.5. 
ECG 
ECG examination will be performed by standard 12-lead at the screening visit for eligibility and 
on Day 0 (prior to dosing and at 4-hour post-dosing), Day 28 ± 1 day (week 4), Day 84 ± 1 (prior 
to dosing and at 4-hour post-dosing, week 12), and Day 168 ± 5 (week 24, EOS/ET).  
7.3.6. 
Bone pain 
Pain is a common problem for men with prostate cancer, but not all men will have pain. The 
most common cause of pain is because cancer has spread to the bones, but even that more than 
25% of men don’t have any pain. If cancer has spread to several other body organs, men often 
only have pain in a few of these organs.  
Bone pain caused by cancer which has spread to the bones has a very specific feeling. Some 
subjects describe it as feeling similar to a toothache but in the bones, or like a dull aching or 
stabbing. Bone pain will be assessed by subject visual assessment scales (VAS) ranging from 1 
(no pain) to 10 (worst possible pain) (see Appendix II), and will be evaluated at baseline (Day 0, 
pre dose), Day 1, Day 7 ± 1 day (week 1), Day 14 ± 1 day (week 2), Day 28 ± 1 day (week 4), 
Day 56 ± 3 days (week 8), Day 84 ± 1 day (pre dose, week 12), Day 112 ± 3 days (week 16), 
Day 140 ± 3 days (week 20), and Day 168 ± 5 days (week 24, EOS/ET).  
7.3.7. 
Urinary signs and symptoms 
Urinary signs and symptoms will be assessed using the International Prostate Symptom Score 
(I-PSS) including 7 questions (See Appendix III). Based on the total score from answering the 7 
questions, the urinary symptom can be assessed as: 1-7 (Mild), 8-19 (Moderate), 20-35 (Severe). 
Urinary signs and symptoms will be evaluated at baseline (Day 0, pre dose), Day 1, Day 7 ± 1 
day (week 1), Day 14 ± 1 day (week 2), Day 28 ± 1 day (week 4), Day 56 ± 3 days (week 8), 
Day 84 ± 1 day (pre dose, week 12), Day 112 ± 3 days (week 16), Day 140 ± 3 days (week 20), 
and Day 168 ± 5 days (week 24). 
7.3.8. 
Adverse events 
Subjects will be asked to report AEs voluntarily. The investigator will also question and examine 
the subjects to identify any AEs at each visit (including screening visit). See Section 9.1 and 
Section 9.2 for detailed information on AEs. 


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7.4. 
Pharmacokinetics Assessment 
7.4.1. 
Pharmacokinetic assessments of LMIS 25 mg 
Pharmacokinetic assessments of LMIS 25 mg will be conducted by measuring the serum 
leuprolide concentration using a validated liquid chromatography-tandem mass spectrometry 
(LC/MS/MS) method. 
To evaluate the sustained castration testosterone level after two doses of LMIS 25 mg injections, 
the PK/PD analysis (serum testosterone and leuprolide levels) in the first enrolled 30 subjects on 
Day 182 (week 26) will also be determined. This additional sampling is meant to assess the 
flexibility of the time period between doses during routine use of LMIS 25 mg and these 30 
subjects will be considered as the subset population for PK analysis. Thus, the first enrolled 30 
subjects will have more intensive sampling to establish the extended PK profile of serum 
leuprolide concentrations by collecting blood samples on Day 0 (prior to the first dose of LMIS 
25 mg, and at 2, 4, and 8 hours post-dose), Days 1, 2, 3, 7, 14, 21, 28, 42, 56, 77, 84 (week 12: 
prior to the second dose and at 2, 4, and 8 hours post the second dose), 85, 86, 87, 98, 112, 126, 
140, 161, 168 (week 24), and 182 (week 26/ EOS/ET).  
The remaining approximately 103 subject will have blood samples collected for determining the 
serum leuprolide concentrations on Day 0 (prior to the first dose of LMIS 25 mg, and 4 hours 
post the first dose), Days 1, 3, 14, 21, 28, 56, 77, 84 (week 12: prior to the second dose and 4 
hours post dose), 85, 86, 87, 98, 112, 140, 161, and 168 (week 24/EOS/ET). 
All blood samples will be collected from subjects by direct venipuncture (approximately 6 mL 
blood per sample). With regard to the time window for blood sample collection, at Visits 6 to 9 
(Day 7 to Day 28), a ± 1-day window is allowed. At Visits 10 and 12 (Day 42 to Day 77), a ± 
3-day window is allowed. At Visits 13 to 16 (Day 84, week 12 visit, for the second dose injection, 
to Day 87), only ± 1-day window is allowed. At Visits 17 to 21 (Day 98 to Day 161), a ± 3-day 
window is allowed. At Visit 22 (Day 168/week 24), a ± 5-day window is allowed. At Visit 23 
(Day 182/week 26), a ±3-day window is allowed. 
All PK/PD blood samples will be centrifuged for serum at 1000  g for 15 minutes as soon as 
possible after collection. The samples will be maintained in an ice bath throughout sample 
collection and preparation. Please see Laboratory Manual for complete instructions. 
All samples will be packed in dry ice and sent to the analytical facility. All shipments will be 
accompanied by an inventory list with other appropriate documents. Additional details of sample 
collection, handling, and processing are outlined in the Laboratory Manual. 
7.4.2. 
Serum sample analysis for Leuprolide Mesylate 
Serum samples collected on the above specified time points will be analyzed for leuprolide 
mesylate using a validated LC/MS/MS method. 
7.4.3. 
Pharmacokinetic analysis of Leuprolide Mesylate 
The pharmacokinetic profile of leuprolide mesylate, including Cmax, Tmax, Cweek4, Cweek12, 
AUC0-week4, AUC0-week12, Cavg(0-week12) will be determined after each dose using Phoenix 
WinNonlin® with non-compartmental approaches.  


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8. 
CONCOMITANT TREATMENT 
All concomitant medications, both permitted and proscribed, and significant non-drug therapies, 
such as surgery, blood transfusions and physical therapy, administered after the subject begins 
participation in this study will be recorded in the source documents and in the concomitant 
treatment log in the CRF. Those records will include generic name / trade names (allowed for 
combination medication only), medical indication, total daily dose, route of administration, and 
start and end dates of treatment. 
Treatments within 6 months prior to the first administration of study drug will be recorded in the 
CRF. Moreover, all concomitant medications administered for the treatment of an AE must be 
recorded. 
8.1. 
Permitted Treatment 
1. Bisphosphonates will be permitted during the study. 
2. Denosumab will be permitted during the study. 
3. Supplementation of vitamin D and calcium will be allowed during the study if, in the 
Investigator’s opinion, it is needed for the subject’s health. 
4. Plain, over-the-counter, multi-vitamins will be permitted during the study. 
5. Glucocorticosteroids will be allowed if being used as a replacement therapy. 
6. Pain medication will be allowed if it is an over-the counter or prescription medication and 
prescribed by a physician and as described in Appendix IV. 
7. Oral hypoglycemics will be allowed for control of Type II diabetes. 
8. Radiation for pain control will be allowed during the study. 
Any use of concomitant treatment must be recorded in the CRF. 
8.2. 
Prohibited Treatment 
The following medications are prohibited during the study period (from screening visit to EOS): 
1. Other gonadotropin-releasing hormones 
2. Other chemotherapy, immunotherapy, cryotherapy, or radiotherapy for treatment of prostate 
cancer 
3. Any OTC medication other than those listed in the Concomitant Treatment section. 
4. Dietary supplements, herbal supplements, or herbal tea. 
5. Insulin 
6. Anti-androgens 
7. 5-alpha reductase inhibitors 
8. Systemic corticosteroids > 10 mg/d 
Subjects who have received these prohibited treatments will be withdrawn from the study. 


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8.3. 
Rescue Medication and Treatment 
In the event of emergency, the investigator will perform clinical life-support procedures according to 
the individual situation. 
 


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9. 
SAFETY MONITORING 
9.1. 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product which does not necessarily have a 
causal relationship with the treatment. An AE can therefore be any unfavorable and unintended 
sign, symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. However, abnormal laboratory values or changes 
are not automatically reported as an AE if they are not clinically significant. They will only be 
recorded as AEs if a therapeutic action is needed or the investigator judges them to be clinically 
significant. 
The occurrence of AEs should be sought by non-directive questioning of the subject at each visit 
and/or telephone follow-up during the study. AEs also may be detected when they are volunteered 
by the subject during or between visits or through physical examination, vital sign measurement, 
laboratory test or other assessments. All AEs must be recorded on the Adverse Events CRF with 
the following information: 
1. AE term and description 
2. Duration (onset and resolution dates or if continuing at final exam) 
3. Severity grade (mild, moderate, severe, life-threatening, death) 
4. Whether the AE constitutes an SAE 
5. Relationship to the study drug (definite/ possible/ unrelated) 
6. Action taken and treatment required 
7. Outcome (recovered/resolved, recovered/resolved with sequelae, recovering/resolving, not 
recovered/not resolved, fetal) 
9.1.1. 
The severity grade of AEs 
The investigator will make an assessment of the maximum intensity that occurred over the duration 
of the event for all AEs reported during the study period using CTCAE version 4. The assessment 
will be based on the investigator’s clinical judgment. The severity of each AE and SAE recorded in 
the CRF should be assigned to one of the categories as described in Table 3. 
 
 


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Table 3 
Intensity Scales of Adverse Events 
 
Severity of AE 
Description 
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 living (ADL)*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
ADL: Activities of Daily Living; AE: Adverse Events 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
9.1.2. 
The relationship to study drug 
The investigator will make an assessment of the relationship between the study drug and the 
occurrence of each AE/SAE. The reasonable possibility of causation will be determined based on 
the investigator’s clinical judgment. The causality should be considered as one of the categories 
described in Table 4. 
The AEs should be followed until resolution or until the event is considered stable. Both regular 
return visits and telephone contacts may be required. 
 
Table 4 
The Relationship between Adverse Events and Occurrence 
 
Relationship 
Description 
Definite 
A clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease 
or other drugs or chemicals.  
Possible 
A clinical event, including laboratory test abnormality, with a reasonable time sequence 
to administration of the drug, but which could also be explained by concurrent disease or 
other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. 
Unrelated 
A clinical event, including laboratory test abnormality, which is clearly not related to 
drug administration. 
 


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9.2. 
Serious Adverse Events  
A serious adverse event (SAE) is any experience that suggests a significant hazard, 
contraindication, side effect or precaution. With respect to human clinical experience, this includes 
any event which: 
 results in death, 
 is life-threatening, 
 requires inpatient hospitalization or prolongation of hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition. 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
 results in persistent of significant disability / incapacity, or 
 is a congenital anomaly / birth defect, 
 is a significant or important medical event that, based on appropriate medical judgment, 
may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed above. 
9.3. 
Serious Adverse Events Reporting Requirement and Emergency 
Procedures 
Any AE which is fatal or life threatening that occurs during the study must be reported promptly 
(within 24 hours) to the sponsor (Foresee) or QPS, irrespective of whether it is related to the use of 
investigational product. If reported to QPS, QPS will inform the sponsor on the same day or at the 
earliest possible time. At the time of the reporting, the following information should be provided if 
possible: study center, subject enrollment number, dose cohort during which the event occurred, a 
description of the event, date of onset and current status, outcome, action taken with the 
investigational drug, the reason why the event is classified as serious, and the Investigator’s current 
assessment of the association between the event and investigational drug. 
Within the required timeframe, the investigator must provide further information on each SAE to 
Foresee/QPS, and QPS will assist the investigator in submitting the SAE to the appropriate 
IRB/EC, ADR reporting center, and Foresee. The SAE/SUSAR (Suspected Unexpected Serious 
Adverse Reaction) will be reported to both competent authorities and relevant IRBs/IECs in 
accordance with the regulatory requirements of the country in which the SAE occurred. 
Each recurrent episode, complication, or progression of the initial SAE should be reported as a 
follow-up to the original episode within 24 hours of the investigator’s receiving the follow-up 


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information. An SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previous one should be reported separately as a new event. 
9.4. 
Pregnancies 
All subjects will be instructed to use adequate contraceptive precautions until the end of study. When 
pregnancy of a subject’s spouse has been discovered, the pregnancy must be reported to 
sponsor/Contract Research Organization (CRO). The pregnancy outcomes, including spontaneous or 
voluntary termination, details of the pregnancy and birth, and the presence or absence of any birth 
defects, congenital abnormalities, or maternal and/or newborn complications, will be followed. The 
infant’s medical record should be followed up to 1 year after birth. 
 


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10. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
10.1. 
Sample Size 
Approximately 133 subjects are expected to be enrolled in this study. A sample size of 120 will 
achieve 85% power to detect a difference (P1-P0) of 0.0700 by using a one-sided binomial test. The 
target significance level is 0.0250. This assumes that the population proportion under the null 
hypothesis is 0.9000 and under the alternative to be 0.97. The estimated drop-out rate is 10%, so 
approximately 13 subjects may drop out from the study before Day 168 (week 24). 
10.2. 
Analysis Population 
In this study, there will be three populations, including intention-to treat (ITT), per protocol (PP), 
and safety populations. The ITT and PP populations will be used for the efficacy analysis. The safety 
population will only be used for the safety analysis. The populations for analysis applied in this study 
are defined as follows: 
1. The Intention-To-Treat (ITT) population will consist of any subject receiving at least one 
dose of LMIS 25 mg. 
2. The Per Protocol (PP) population will be composed of those subjects who received 2 doses of 
LMIS 25 mg without major deviations that will impact the assessment of the primary 
efficacy endpoint. 
3. The safety population will consist of any subject receiving a dose of LMIS 25 mg. 
10.3. 
Analysis Method 
For descriptive statistics, continuous variables will be presented as number of observations, mean, 
standard deviation (SD), median, range, Hodges-Lehmann estimator, and 95% CI. 
Categorical variables will be presented by frequency and percentage. 
Changes from baseline will be tested by paired t-test or Wilcoxon signed-rank test for continuous 
variables using a significance level of 0.05. 
10.4. 
Efficacy Analysis 
The efficacy analysis will be based on the following endpoints assessments in both ITT and PP 
populations. 
10.4.1. 
Analysis of primary endpoint 
The primary endpoint of efficacy is to determine the percentage of subjects with a serum testosterone 
concentration suppressed to castrate levels (≤ 50 ng/dL) on Day 28 ± 1 day (week 4) following the 
first injection of LMIS 25 mg and to determine the proportion of subjects with serum testosterone 
suppression (≤ 50 ng/dL) from Day 28 ± 1 day (week 4) through Day 168 ± 5 days (week 24) until 
the end of the study. 
The percentage of subjects with a serum testosterone concentration suppressed to castrate levels (≤ 
50 ng/dL) on Day 28 ± 1 day (week 4) and on Day 168 ± 5 days (week 24) will be analyzed using a 


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standard large sample approximation to a Binomial distribution. The percentage of subjects with 
testosterone suppression (≤ 50 ng/dL) from Day 28 (week 4) through Day 168 ± 5 days (week 24) 
will be analyzed using the Kaplan-Meier approach. 
Insufficient testosterone suppression is defined as suppression that does not occur by Day 28 (week 
4) or occurrence of a testosterone level >50 ng/dL between Day 28 (week 4) and Day 168 (week 
24). 
The following efficacy analyses will be provided in detail in the statistical analysis plan: 
• 
The proportion of subjects with testosterone suppression (≤ 50 ng/dL) from Day 28 
(week 4) through Day 168 ± 5 days (week 24)  
• 
Subjects exhibiting post-suppression breakthrough of serum testosterone to >50 
ng/dL 
• 
Time to event: A subject with a testosterone level > 50 ng/dL between Days 28 and 
168 is considered to have an event.  
To accommodate drop-out and missing values, the data censoring rules is shown in Table 5. 
10.4.2. 
Analysis of secondary endpoints 
The analyses of secondary endpoints will be based on the following: 
• 
The mean acute-on-chronic (surge) changes in testosterone and LH levels from just 
prior to the second injection through 14 days after the second injection of LMIS 25 
mg (Day 98, week 14)   
The mean acute-on-chronic changes in serum testosterone concentration will be summarized by 
descriptive statistics. The change from baseline will be summarized descriptively and a paired t-test 
or Wilcoxon signed-rank test will be used, data significance level of 0.05.  
• 
Effect of LMIS 25 mg on change of serum prostate-specific antigen (PSA) levels  
• 
Effect of LMIS 25 mg on change of serum LH levels 
The serum PSA levels and serum LH levels during the study will be summarized as descriptive 
statistics. The mean acute-on-chronic changes in LH level from after the 2nd injection of LMIS 25 
mg will be summarized descriptively. The change from baseline will be summarized descriptively 
and a paired t-test or Wilcoxon signed-rank test will be used, data significance level of 0.05.  
• 
The percentage of subject with PSA relapse defined as after achieving the serum 
PSA level ≤ 4 ng/mL post LMIS 25 mg injection but with an increase in serum PSA 
of >50% PSA nadir by Day 168 (week 24). A post hoc analysis will be performed to 
determine the incidence of PSA recurrence. 
The incidence of PSA relapse is defined as after achieving serum PSA level ≤ 4 ng/mL post LMIS 
25 mg injection but with an increase in serum PSA > 50% compared with nadir will be presented 
as a count, percentage, and 95% Cl. 
• 
The percentage of subject achieving normal serum PSA level (<4 ng/dL) on Day 
168 ± 5 days (week 24) 
The number of subjects achieving normal serum PSA level (<4 ng/dL) on Day 168 ± 5 days (week 
24) will be presented as a count, percentage, and 95% Cl. 


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• 
The percentage of subjects achieving enhanced serum testosterone concentration 
suppression to ≤ 20 ng/dL on Day 28 ± 1 day (week 4) and on Day 168± 5 days 
(week 24). 
The percentage of subjects with an enhanced serum testosterone suppression to ≤ 20 ng/dL by Day 
28 ± 1 day (week 4) and Day 168 ± 5 days (week 24) will be analyzed using a standard large 
sample normal approximation to a Binomial distribution. 
Table 5 
Data Censoring Rules 
 
Subject 
Discontinued 
Day 28- 168 or Day of 
Discontinuation 
To Be Handled As 
More Than 1 
Missing 
Testosterone 
Value 
Any Escape 
Yes 
No 
No 
Censored on day of last measurement 
Yes 
No 
Yes 
Event on day of first escape 
Yes 
Yes 
No 
Censored on day of last measurement before 
the first missing 
Yes 
Yes 
Yes 
Event on day of first escape 
No 
No 
No 
Censored on Day 168 
No 
No 
Yes 
Event on day of first escape 
No 
Yes 
No 
Censored on day of last measurement before 
the first missing 
No 
Yes 
Yes 
Event on day of first escape 
No suppression by Day 28 
Event on Day 28 
 
 
 


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10.5. 
Safety Analysis 
The safety analysis of LMIS 25 mg will be based on the following safety assessments: 
• 
Adverse event (AE)/serious adverse event (SAE) reporting 
The analysis of AEs will be tabulated by system organ class (SOC) and preferred terms according 
to the current MedDRA dictionary. Preferred terms will be used and presented as standardized 
tabulations by frequency and incidence rates. AE incidence rates will be analyzed by severity and 
relationship to study drug. Any AE leading to death, discontinuation from the study, or change of 
dose will be listed as per regulations. If any SAE occurs, a summary of the SAEs will be described 
and listed. 
• 
Assessment of injection site reaction 
The local injection site reaction will be summarized descriptively. 
• 
Change in bone pain measurement (by Visual Analogue Scale [VAS] scale) 
• 
Change in urinary signs and symptoms and the total score between baseline (Day 0) 
and Day 168 ± 5 (days, week 24) (by the International Prostate Symptom Score, I-PSS 
sheet) 
The summary results of bone pain measurement (by VAS scale) at baseline (Day 0), end of study 
visit (EOS/ET, Day 168 ± 5 days, week 24), and the change from baseline will be summarized 
descriptively. The change from baseline to EOS visit will be tested by paired t-test or Wilcoxon 
signed-rank test at a significance level of 0.05. The urinary signs and symptoms (by the 
International Prostate Symptom Score, I-PSS, sheet) at baseline (Day 0) and EOS/ET visit (Day 
168 ± 5 days, week 24) will be summarized descriptively 
• 
Change in vital signs (BP, HR, RR, weight) 
• 
Change in physical examinations with clinical significance compared to baseline by 
principal investigator’s judgment  
The summary results of change in physical examinations with clinical significance vital signs (BP, 
HR, RR) and weight at baseline (Day 0), EOS/ET Visit (Day 168 ± 5 days, week 24), and the 
change from baseline will be summarized descriptively. Also the change from baseline (Day 0) to 
the EOS/ET Visit (Day 168 ± 5 days, week 24), will be tested by paired t-test or Wilcoxon 
signed-rank test at a significance level of 0.05. The transition matrix of physical examination and 
change in vital signs will be summarized. 
• 
Change in lab data, including liver function (AST, ALT, ALP), renal function 
(BUN, SCr), complete blood count with platelets, clinical chemistries (K, Na, Mg, 
Ca and P), urinalysis, serum glucose, lipid profile (LDL, HDL, triglycerides), and 
HbA1c level 
The summary results of laboratory data at baseline (Day 0) and the EOS Visit (Day 168 ± 5 days, 
week 24) and change from baseline (Day 0) to the EOS/ET Visit (Day 168 ± 5 days, week 24) will 
be summarized by descriptive statistics and paired t-test or Wilcoxon signed- rank test and will be 
used at a significance level of 0.05. The transition matrix of change in laboratory data between 
baseline (Day 0) and the EOS/ET Visit (Day 168 ± 5 days, week 24) will be summarized. 


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• 
Clinically significant changes in 12-lead resting electrocardiogram (ECG) per the 
investigator’s judgment 
The summary results of 12-lead resting ECG at baseline (Day 0) and the EOS/ET Visit (Day 168 ± 5 
days, week 24) will be summarized descriptively. The transition matrix for ECGs will be 
summarized. 
10.6. 
Pharmacokinetics Analysis 
The pharmacokinetic profile of leuprolide mesylate will be determined in a sub-set of subjects (first 
30 subjects enrolled) through more intensive PK sampling. PK analyses will also be conducted for 
other subjects as well and results will be used as supporting data.  
The serum pharmacokinetic profile of leuprolide following 2 subcutaneous injections of LMIS 25 
mg given 12 weeks apart will be determined from baseline (Day 0) to Day 168 (week 24). The 
serum pharmacokinetic/pharmacodynamics levels of leuprolide, testosterone, and LH will be 
followed for additional 2 weeks post Day 168 (Day 182, week 26) in the first enrolled 30 subjects 
to evaluate the PK/PD relationship between LMIS 25 mg and the sustained castration testosterone 
level after two doses of LMIS 25 mg injections. 
The PK parameters of leuprolide will be determined during the study period, including Cmax, Tmax, 
Cweek4, Cweek12, AUC0-week4, AUC0-week12, Cavg(0-12 week) after each dose. The Day 182 (week 26) 
leuprolide serum concentration data will also be assessed in the first enrolled 30 subjects (PK 
sub-set). The pharmacokinetic parameters of leuprolide (Table 6) will be calculated from the serum 
concentrations collected during the study. Phoenix WinNonlin®  will be used for the pharmacokinetic 
analyses using a non-compartmental analysis model. 
Table 6 
Pharmacokinetic analysis of leuprolide mesylate in all subjects 
 
Term 
Definition 
Cmax 
Maximum observed serum concentration  
Tmax 
Time to the maximum serum concentration 
Cweek4 
Observed serum concentration at 4 weeks (approximately 28 days) post 
dosing 
Cmonth3 
Observed serum concentration at 12 weeks (approximately 84 days) 
post dosing 
AUC0-week4 
Area under the concentration-time curve calculated using the linear 
up/log down trapezoidal method from time zero to 4 weeks 
(approximately 28 days) post dosing 
AUC0-week12 
Area under the concentration-time curve calculated using the linear 
up/log down trapezoidal method from time zero to week 12 
(approximately 84 days) post dosing 
Cavg(0-week12) 
Mean serum concentration within 12 weeks (approximately 84 days) 
post dosing 
avg: average; max: maximum;  


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Statistical analyses will be performed for serum leuprolide using the SAS system for Windows or 
Phoenix WinNonlin®. Arithmetic means, SD, and coefficients of variation will be calculated for the 
pharmacokinetic parameters listed above. 
For the pharmacokinetic assessment of leuprolide, all measured values below quantifiable limit 
(BQL) will be set to zero for all pharmacokinetic and statistical evaluation. Any missing samples will 
be reported as ‘NS’ and will not be included for pharmacokinetic or statistical analysis. 
10.7. 
Handling of Missing Values 
For handling missing data related to a safety or efficacy endpoints, no missing data method will be 
performed. Some situations are noted for efficacy analysis by Kaplan-Meier method: 
1. The subject has an event and it will be analyzed as an event on the day of first testosterone 
escape. 
2. The subject with more than one missing testosterone value will be censored on the day of last 
measurement 
3. Any subject having more than one missing testosterone values will be censored on the day 
with the last measurement before the first missing testosterone measurement 
4.  If subject does not have serum testosterone suppression to castrate level (i.e. serum 
testosterone levels > 50 ng/dL) by Day 28 (week 4), the event date will be set as Day 28 for 
the analysis of percentage of subjects with testosterone suppression (≤ 50 ng/dL) from Day 
28 (week 4) through Day 168 (week 24). 


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11. 
STUDY ADMINISTRATIVE STRUCTURE 
11.1. 
Ethical Conduct of the Study 
The study will be performed in accordance with the protocol, ICH Harmonized Tripartite 
Guidelines for Good Clinical Practice (GCP) and applicable local regulations. 
The US FDA has eliminated all reference to the Declaration of Helsinki since 2006 and uses the 
ICH Guidelines for GCP in addition to 21 CFR 50 and 21 CFR 56. The study will be conducted in 
compliance with 21 CFR 312 and 54 (financial disclosure). For the US sites those regulatory 
documents are considered primary. 
In general, and for other regions of the world, the Declaration of Helsinki 7th revision (2013) and/or 
the ICH Guidelines for GCPs will be considered primary documents for this study, unless local or 
regional regulatory preferences dictate otherwise. 
11.2. 
Institutional Review Board (IRB) / Ethics Committee (EC) 
The principal investigator will provide the IRB or EC with all appropriate essential documents, 
including the protocol and the informed consent document. The trial will not be initiated until 
appropriate IRB or EC approval of the appropriate essential documents is received by the 
investigator and the sponsor (Foresee). In addition, the investigator is responsible for reporting 
SAEs, as defined in the protocol, to the IRB/IEC at each investigational site/study center according 
to the applicable, local regulations. 
11.3. 
Informed Consent Process and Subject Information 
A properly executed written informed consent in the applicable local language will be obtained 
from each subject prior to the subject’s entrance into the trial and prior to performance of any 
procedure that involves risk to the subject.  
Each investigator will provide a copy of the IRB-approved informed consent to every subject and a 
signed copy shall be maintained in the subject’s record file. The basic elements will be 
incorporated into the informed consent according to the International Conference on 
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), 21 CFR 50 and 21 CFR 56 (in 
the US) and in accordance with the Declaration of Helsinki 7th revision (2013) in areas of the world 
where this is recognized. The information will include the experimental setting, trial objectives, 
possible benefits, side effects and dangers of participation in the trial, currently available 
alternative procedures or treatment regimens, the rights and responsibilities of the trial subject, and 
other information that is relevant to the subject’s decision to participate. 


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12. 
INSURANCE AND INDEMNITY 
All subjects will be insured by Foresee against complications of any kind which are directly caused 
by the administration of the investigational drug or the study procedures. Information regarding 
insurance and indemnity will be provided to the investigators by the sponsor prior to the initiation 
of this trial. 
 


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13. 
SOURCES DOCUMENTS 
To enable evaluations and/or audits from health regulatory authorities, QPS or Foresee, the 
investigator will agree to keep secure records that include the identity of participating subjects, 
original signed Informed Consent Forms (ICFs), copies of CRFs and detailed records of medication 
disposition and study procedures. The principal investigator must maintain all documentation 
relating to the study according to the national law or regulations for a period of 2 years after the 
last marketing application approval, or if not approved 2 years following the discontinuance of the 
test article for investigation. The investigator and Foresee will retain the subjects’ identification 
and all trial-related documents according to the appropriate regulatory authorities and the 
requirements of the sponsor. No records will be destroyed by the clinical sites without the written 
consent from Foresee Pharmaceuticals.  
All information provided to the investigator by the sponsor, including pre-clinical data, the 
protocols and any other information should be kept confidential and confined to the clinical 
personnel involved in conducting the study or authorized representatives of appropriate 
health/regulatory authorities. Identity, hospital records, and site records of each subject will also 
kept confidential except for authorized personnel. 


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14. 
CASE REPORT FORM 
It is Foresee’s policy that all study data must be verifiable to the source data, which necessitates 
access to all original recordings, laboratory reports, and subjects’ records. The investigator must 
agree to allow access to the subjects’ records and source data by Foresee, QPS, the IRB/EC and 
Health Authorities personnel. The subjects must also agree to allow access to the subjects’ medical 
records. Subjects will provide written consent before this action is taken. Correction to data on 
source data may be made only by putting a line through the incorrect data and writing the correct 
values, allowing the original text to remain legible. Each correction must be initialed and dated by 
the person making the change. If corrections are made after review and signature by the 
investigator, the investigator must be made aware of the changes. 
 


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15. 
CONTROL AND ASSURANCE OF STUDY QUALITY 
15.1. 
Assignment of Site Monitor 
All aspects of the study will be conducted under ICH GCP and FDA guidelines. Qualified 
individuals designated and approved by QPS and the sponsor will monitor the study. Monitoring 
will be conducted according to GCP and standard operating procedures for compliance with 
applicable government regulations. The investigator will agree to allow these monitors access to 
the study and medical files for the subjects, the clinical supplies, the IP dispensation documents, 
and the test drug storage areas and, if requested, agree to assist the monitors. 
15.2. 
Data Quality Assurance 
The study will be monitored by regular site visits and telephone calls to the investigator by QPS, 
QPS contractors, and/or Foresee representatives as outlined in the Monitoring Plan. During the site 
visits, the monitor will review original subject records, drug accountability records, and the study 
file. The monitor will also meet with the investigator to discuss the study status and any issues. 
15.3. 
Audits and Inspections 
Auditors, authorized representatives from Foresee Pharmaceuticals, an IRB or an IEC; and/or 
inspectors from a regulatory authority may visit the site to perform audits or inspections. The 
purpose of an audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed and accurately reported according to the protocol, Good Clinical Practice 
guidelines of the International Conference on Harmonization (ICH), and any applicable regulatory 
requirements. The investigator should contact Foresee Pharmaceuticals or QPS, LLC immediately 
if contacted by a regulatory agency for an inspection or by IRB/IEC for an audit. 


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16. 
PROTOCOL DEVIATION / VIOLATION 
All deviations from the protocol should be reported to QPS. This includes, but is not limited to, the 
following: 
1. Subjects who entered the study but did not satisfy all entry criteria; 
2. Subjects who satisfied the criteria for one or more of the withdrawal reasons during the study 
but were not withdrawn; 
3. Subjects who received the wrong treatment or incorrect dose; 
4. Subjects who received concomitant treatment in an incorrect manner or who received a 
non-approved concomitant treatment. 
5. Subjects who missed the sample collection for efficacy assessment on the scheduled visit 
Examples include subject noncompliance with medication, surreptitious use of medications 
prohibited by the protocol, inability, or unwillingness to accurately report AEs or concomitant 
medication use. Additionally, exceptions or deviations that could conceivably affect the collection 
or interpretation of the data related to safety or efficacy assessments should also be reported. 


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17. 
PROTOCOL AMENDMENTS 
Only Foresee may modify the protocol. Amendments to the protocol will only be made after 
consultation and agreement between Foresee, QPS, and the investigator. All amendments that have 
an impact on subject risk, safety, or the study objectives, or require revision of the informed 
consent document, must receive approval from the appropriate IRB/EC prior to its implementation. 


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18. 
COMPLETION OF STUDY 
This study will be completed after all subjects completed the end of the 6-month visit (Day 
168/week 24 or Day 182/ week 26 in the first enrolled 30 subjects). 


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19. 
TERMINATION OF STUDY 
Foresee Pharmaceuticals reserves the right to discontinue this trial at any time. If the study is 
prematurely terminated or suspended, the PI will promptly inform the IRB/IEC and will provide 
the reason(s) for the termination or suspension. Foresee Pharmaceuticals or the designated 
representative will promptly inform the regulatory authority. 


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20. 
RETENTION OF RECORDS AND CONFIDENTIALITY 
Clinical investigators are responsible for maintaining study information (e.g., the original signed 
Informed Consent, copies of CRFs, and detailed records of medication disposition) pertaining to 
the subject’s identity in a confidential manner. If the need arises, only Foresee, QPS, or appropriate 
regulatory/health authorities will have access to this information. 


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21. 
USE OF INFORMATION AND PUBLICATION 
No part of the study protocol or its amendments, nor any information given by Foresee or QPS to 
the investigators for the purpose of evaluating and/or performing the study, shall be disclosed to 
any third party without prior written consent from Foresee. The investigator is obliged to provide 
Foresee and QPS with copies of all data derived from the study. Except for when required by law, 
only Foresee has the sole right to disclose the study information to other physicians and regulatory 
agencies. 


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22. 
REFERENCES 
1. Jemal, A., et al., Global cancer statistics. CA Cancer J Clin, 2011. 61(2): p. 69-90. 
2. Society, A.C., American Cancer Society: Cancer Facts and Figures 2013. 2013. 
3. Huggins, C. and C.V. Hodges, Studies on prostatic cancer: I. The effect of castration, of 
estrogen and of androgen injection on serum phosphatases in metastatic Cancer of the 
prostate. 1941. J Urol, 2002. 168(1): p. 9-12. 
4. Sasse, A.D., et al., Androgenic suppression combined with radiotherapy for the treatment of 
prostate cancer: a systematic review. BMC Cancer, 2012. 12: p. 54. 
5. Tamburrino, L., et al., Androgen receptor (AR) expression in prostate cancer and progression 
of the tumor: Lessons from cell lines, animal models and human specimens. Steroids, 2012. 
77(10): p. 996-1001. 
6. Liu, S.V., S. Liu, and J. Pinski, Luteinizing hormone-releasing hormone receptor targeted 
agents for prostate cancer. Expert Opin Investig Drugs, 2011. 20(6): p. 769-78. 
7. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. The Leuprolide Study 
Group. N Engl J Med, 1984. 311(20): p. 1281-6. 
8. Fujino, M., et al., Synthetic analogs of luteinizing hormone releasing hormone (LH-RH) 
substituted in position 6 and 10. Biochem Biophys Res Commun, 1974. 60(1): p. 406-13. 
9. Tunn, U.W., A 6-month depot formulation of leuprolide acetate is safe and effective in daily 
clinical practice: a non-interventional prospective study in 1273 subjects. BMC Urol, 2011. 
11: p. 15. 
10. Abouelfadel, Z. and E.D. Crawford, Leuprorelin depot injection: subject considerations in 
the management of prostatic cancer. Ther Clin Risk Manag, 2008. 4(2): p. 513-26. 
11. Bourdin, S., et al., Clinical experience with leuprorelin acetate before radiotherapy for 
prostatic cancer. J Int Med Res, 1990. 18 Suppl 1: p. 74-8. 
12. Crawford, E.D. and J.M. Phillips, Six-month gonadotropin releasing hormone (GnRH) 
agonist depots provide efficacy, safety, convenience, and comfort. Cancer Manag Res, 2011. 
3: p. 201-9. 
13. Prezioso, D., et al., Leuprorelin 1-month depot as neoadjuvant therapy for prostate cancer. 
Takeda NHT Italian Group. Urol Int, 1998. 60 Suppl 2: p. 11-7; discussion 35. 
14. Sharifi, R., et al., Leuprolide acetate 22.5 mg 12-week depot formulation in the treatment of 
subjects with prostate cancer. Clin Ther, 1996. 18(4): p. 647-57. 
15. Sharifi, R., et al., Leuprolide acetate (30-mg depot every four months) in the treatment of 
prostate cancer. Urology, 1998. 51(2): p. 271-6. 
16. Spitz, A., et al., Efficacy and safety of leuprolide acetate 6-month depot for suppression of 
testosterone in subjects with prostate cancer. Prostate Cancer Prostatic Dis, 2012. 15(1): p. 
93-9. 


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17. Crawford, E.D., et al., A 12-month clinical study of LA-2585 (45.0 mg): a new 6-month 
subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancer. J 
Urol, 2006. 175(2): p. 533-6. 
18. Sethi, R. and N. Sanfilippo, Six-month depot formulation of leuprorelin acetate in the 
treatment of prostate cancer. Clin Interv Aging, 2009. 4: p. 259-67. 
19. Lee S, Lee H, Kim S,. et al., Is high-dose leuprorelin acetate effective and safe in Asian men 
with prostate cancer? An open-label, non-comparative, multi-center clinical trial. Yonsei 
Med J. 2014; 55(2):310-5.  
 
 


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APPENDIX I 
DECLARATION OF HELSINKI 
World Medical Association Declaration of Helsinki – Ethical Principles for Medical Research 
Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Introduction 
The World Medical Association has developed the Declaration of Helsinki as a statement of ethical 
principles to provide guidance to physicians and other participants in medical research involving 
human subjects. Medical research involving human subjects includes research on identifiable human 
material or identifiable data. 
It is the duty of the physician to promote and safeguard the health of the people. The physician’s 
knowledge and conscience are dedicated to the fulfilment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with the words, 
"The health of my subject will be my first consideration," and the International Code of Medical 
Ethics declares that, "A physician shall act only in the subject's interest when providing medical 
care which might have the effect of weakening the physical and mental condition of the subject." 
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of 
disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously 
be challenged through research for their effectiveness, efficiency, accessibility and quality. 
In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic 
procedures involve risks and burdens. 


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Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights. Some research populations are vulnerable and need special 
protection. The particular needs of the economically and medically disadvantaged must be 
recognized. Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care. 
Research Investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international requirements. 
No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of 
the protections for human subjects set forth in this Declaration.  
 
Basic Principle for All Medical Research  
 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the 
human subject. 
Medical research involving human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and on adequate laboratory and, where appropriate, animal experimentation. 
Appropriate caution must be exercised in the conduct of research which may affect the environment, 
and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol. This protocol should be submitted for consideration, 
comment, guidance, and where appropriate, approval to a specially appointed ethical review 
committee, which must be independent of the Investigator, the sponsor or any other kind of undue 
influence. This independent committee should be in conformity with the laws and regulations of the 
country in which the research experiment is performed. The committee has the right to monitor 
ongoing trials. The researcher has the obligation to provide monitoring information to the committee, 
especially any SAEs. The researcher should also submit to the committee, for review, information 
regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and 
incentives for subjects. 
The research protocol should always contain a statement of the ethical considerations involved and 
should indicate that there is compliance with the principles enunciated in this Declaration. 
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility for 
the human subject must always rest with a medically qualified person and never rest on the subject of 
the research, even though the subject has given consent. 
Every medical research project involving human subjects should be preceded by careful assessment 
of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. 
This does not preclude the participation of healthy volunteers in medical research. The design of all 
studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be satisfactorily 


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managed. Physicians should cease any investigation if the risks are found to outweigh the potential 
benefits or if there is conclusive proof of positive and beneficial results. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject. This is especially important when 
the human subjects are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations in which the 
research is carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed participants in the research project. 
The right of research subjects to safeguard their integrity must always be respected. Every precaution 
should be taken to respect the privacy of the subject, the confidentiality of the subject’s information 
and to minimize the impact of the study on the subject's physical and mental integrity and on the 
personality of the subject. 
In any research on human beings, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. 
The subject should be informed of the right to abstain from participation in the study or to withdraw 
consent to participate at any time without reprisal. After ensuring that the subject has understood the 
information, the physician should then obtain the subject's freely-given informed consent, preferably 
in writing. If the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
When obtaining informed consent for the research project, the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under duress. 
In that case the informed consent should be obtained by a well-informed physician who is not 
engaged in the investigation and who is completely independent of this relationship. 
For a research subject who is legally incompetent, physically or mentally incapable of giving consent 
or is a legally incompetent minor, the investigator must obtain informed consent from the legally 
authorized representative in accordance with applicable law. These groups should not be included in 
research unless the research is necessary to promote the health of the population represented and this 
research cannot instead be performed on legally competent persons.  
 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions 
about participation in research, the investigator must obtain that assent in addition to the consent of 
the legally authorized representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy or advance 
consent, should be done only if the physical/mental condition that prevents obtaining informed 
consent is a necessary characteristic of the research population. The specific reasons for involving 
research subjects with a condition that renders them unable to give informed consent should be stated 
in the experimental protocol for consideration and approval of the review committee. The protocol 
should state that consent to remain in the research should be obtained as soon as possible from the 
individual or a legally authorized surrogate. 
Both authors and publishers have ethical obligations. In publication of the results of research, the 
investigators are obliged to preserve the accuracy of the results. Negative as well as positive results 


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should be published or otherwise publicly available. Sources of funding, institutional affiliations and 
any possible conflicts of interest should be declared in the publication. Reports of experimentation 
not in accordance with the principles laid down in this Declaration should not be accepted for 
publication.  
 
Additional Principles for Medical Research Combined With Medical Care  
The physician may combine medical research with medical care, only to the extent that the research 
is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is 
combined with medical care, additional standards apply to protect the subjects who are research 
subjects. 
The benefits, risks, burdens and effectiveness of a new method should be tested against those of the 
best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of 
placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method 
exists. (See footnote*) 
At the conclusion of the study, every subject entered into the study should be assured of access to the 
best proven prophylactic, diagnostic and therapeutic methods identified by the study. 
The physician should fully inform the subject which aspects of the care are related to the research. 
The refusal of a subject to participate in a study must never interfere with the subject-physician 
relationship. 
In the treatment of a subject, where proven prophylactic, diagnostic and therapeutic methods do not 
exist or have been ineffective, the physician, with informed consent from the subject, must be free 
to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician’s 
judgement it offers hope of saving life, re-establishing health or alleviating suffering. Where 
possible, these measures should be made the object of research, designed to evaluate their safety 
and efficacy. In all cases, new information should be recorded and, where appropriate, published. 
The other relevant guidelines of this Declaration should be followed.  
 
*FOOTNOTE: 
Note of Clarification on Paragraph 29 of the WMA Declaration of Helsinki 
 
The WMA hereby reaffirms its position that extreme care must be taken in making use of a 
placebo-controlled trial and that in general this methodology should only be used in the absence of 
existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if 
proven therapy is available, under the following circumstances: 
- Where for compelling and scientifically sound methodological reasons its use is necessary to 
determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or 
- Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition 
and the subjects who receive placebo will not be subject to any additional risk of serious or 
irreversible harm.  
 
All other provisions of the Declaration of Helsinki must be adhered to, especially the need for 
appropriate ethical and scientific review.


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APPENDIX II 
Visual Analogue Scale 
(VAS) 
The visual analog scale (VAS) is a unidimensional measure of pain intensity in adults. For this 
scale, subjects indicate their current level of pain along a 10 cm line with ‘no pain’ at one end and 
‘worst pain imaginable’ at the other. The VAS score is determined by measuring the line in 
centimeters from the left end to the point that the subject marks his degree of pain. 
Instructions for producing a VAS Card: 
• 
Print or photocopy the diagrams to ensure that the line is exactly 10 cm in length. 
• 
Advice the subject marks on the line to the point that they feel represents their perception 
of their current painful states. 
 
 
Subject Name: ________________ Enrollment number: ________ 
Date completed (dd-mon-year): _______ Visit number: _______ 
 
 
 
 
 
 
 
 
 
 


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APPENDIX III 
International Prostate Symptom Score (I-PSS) (1/2) 
Subject Name: ______________ Enrollment number: ________  
Date completed (dd-mon-year): _______ Visit number: _______ 
Please circle one number in the following questions. 
In the past month 
Not at All 
Less Than 1 in 
5 Times  
Less than Half 
the Time 
About Half 
the Time 
More Than 
Half The 
Time 
Almost 
Always 
1. Incomplete Emptying: how 
often have you had the sensation of 
not emptying your bladder? 
0 
1 
2 
3 
4 
5 
2. Frequency: how often have you 
had to urinate again in less than 2 
hours after you finished urinating? 
0 
1 
2 
3 
4 
5 
3. Intermittency: how often have 
you found you stopped and started 
again several times when you 
urinated  
0 
1 
2 
3 
4 
5 
4. Urgency: how often have you 
found it difficult to postpone 
urination? 
0 
1 
2 
3 
4 
5 
5. Weak Stream: how often have 
you had a weak urinary stream? 
0 
1 
2 
3 
4 
5 
6. Straining: how often have you 
had to strain to start urination? 
0 
1 
2 
3 
4 
5 
 
None 
1 Time 
2 Times 
3 Times 
4 Times 
5 or More 
Times 
7. Nocturia: how many times did 
you typically get up to urinate 
during the night? 
0 
1 
2 
3 
4 
5 
Total I-PSS Score (Add number from question 1 
to 7)  
 
 
 


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International Prostate Symptom Score (I-PSS) (2/2) 
Quality of Life Due to Urinary Symptoms: 
Subject Name: ______________ Enrollment number: ________  
Date completed (dd-mon-year): _______ Visit number: _______ 
Circle One Number in the Next Row 
Delighted 
Pleased 
Mostly 
Satisfied 
 
Mixed 
Mostly 
Dissatisfied 
Unhappy 
 
Terrible 
If you were to spend the rest of 
your life with your urinary 
condition just the way it is now, 
how would you feel about that? 
0 
1 
2 
3 
4 
5 
6 
 
Name of CRC: __________________ Signature of CRC: ________________________  
 
Date: _____________  
OR 
Name of PI: _____________________ Signature of PI: _______________________  
 
 
Date: _____________  
 
PI: Principal investigator 
 
!Please keep this questionnaire in the subject folder! 
 
 
 
 
 


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APPENDIX IV 
Pain in cancer subjects within the trial should be treated properly and sufficiently. The list of allowed 
medication in the three-step pain treatment, including recommended dosage, is attached. OTC 
medicines are allowed if they are included on the below list. Herbal products are prohibited. 
Treatment with NSAIDs (non-steroidal anti-inflammatory drugs) should be covered by parallel 
application of potent proton pump inhibitors (e.g. Omeprazole) in sufficient dosage according to the 
product’s package insert or the SPC (Summary of Product Characteristics-EU). 
List of the allowed medication in alphabetical order follows: 
Acetaminophen (paracetamol), Aspirin, Buprenorphine, Butorphanol, Celecoxib, Codeine, 
Diclofenac, Diflunisal, Dihydrocodeine, Etodolac, Fenoprofen, Fentanyl buccal tablet, Fentanyl 
transdermal system, Fentanyl citrate oral transmucosal (OTFC), Flurbiprofen, Hydrocodone, 
Hydromorphone, Choline magnesium trisalicylate, Ibuprofen, Indomethacin, Ketoprofen, 
Ketorolac, Levorphanol, Meclofenamic acid, Mefenamic acid, Meloxicam, Meperidine (Pethidine), 
Methadone, Morphine, Morphine (Modified-release), Nabumetone, Nalbuphine, Naproxen, 
Naproxen sodium, Oxaprozin, Oxycodone, Oxycodone (Modified-release), Oxymorphone, 
Oxymorphone (Modified-release), Pentazocine, Phenylbutazone, Piroxicam, Propoxyphene (HCI 
and napsylate), Salsalate, Sulindac, Tolmetin, Tramadol. 
 
Three-Step Pain Treatment for Foresee FP01C-17-001 Clinical Trial 
Adjusted according to guidelines: 
Russell K. Portenoy: Three-step analgesic ladder for management of cancer pain; Dept. of Pain 
Medicine and Palliative care, Beth Israel Medical Center, New York, New York 
ALLOWED MEDICATIONS FOR PAIN, DOSAGES AND SCHEDULE: 
First Step 
 
NONOPIOID ANALGESICS FOR MILD TO MODERATE PAIN 
Class 
Generic Name 
Dosing Schedule Recommended 
Starting Dose 
mg/d* 
Maximum  
 
Salsalate 
q12h 
1,500 x 
1, then 
1,000 
q12h 
4,000 
Propionic acids § 
Fenoprofen+ 
q4-6h 
800 
3,200 
Flurbiprofen 
q8-12h 
100 
300 
Ibuprofen+ 
q4-8h 
1,200 
3,200 


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Class 
Generic Name 
Dosing Schedule Recommended 
Starting Dose 
mg/d* 
Maximum  
Ketoprofen+ 
q6-8h 
150 
300 
 
Naproxen+ 
q12h 
500 
1,000 
Naproxen 
sodium+ 
q12h 
550 
1,100 
Oxaprozin 
q24h 
600 
1,800 
Acetic acids 
Diclofenac 
q6h 
150  
200 
Etodolac+ 
q6-8h 
600 
1,200 
Indomethacin 
q8-12h 
75 
200 
Ketorolac+ 
q6h 
15-30 q6h 
I.V., IM 
10 q6h PO 
120 I.V., IM 
40 PO 
Sulindac 
q12h 
300 
400 
Tolmetin 
q6-8h 
600 
1,800 
Naphthylalkanone Nabumetone 
q24h 
1,000 
2,000 
Oxicams§ 
Meloxicam 
q24h 
7.5 
15 
Piroxicam 
q24h 
20 
40 
Fenametes§ 
Meclofenamic 
acid+ 
q6-8h 
150 
400 
 
Mefenamic 
acid+ 
q6h 
500 x 1, 
Then 250 
q6h 
1,000 
Pyrazole§ 
Phenylbutazone q6-8h 
300 
400 
 
 
 
 


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Second Step 
 
SHORT/ACTING OPIOIDS For Moderate Pain 
Class 
Generic Name 
Dose 
(mg) II 
Peak Effect, h 
Duration, h 
Morphine-like 
agonists 
Codeine 
32-65 
 
1.5-2 
3-6 
Dihydrocodeine 
15-20 
- 
4-5 
Hydrocodone 
- 
0.5-1 
4-6 
Meperidine 
(pethidine) 
50 
1-2 
3-5 
Oxycodone 
2.5 
1 
3-6 
Propoxyphene HCI 
65-130 
2-2.5 
3-6 
Propoxyphene 
napsylate 
100-200 
2-2.5 
3-6 
Agonist-antagonist Pentazocine 
30 
1.5-2 
2-4 
Other 
Tramadol 
- 
2-3 
4-6 
 
Third Step 
 
SHORT- AND LONG-ACTING OPIOIDS for Moderate to Severe Pain 
Class 
Generic Name 
Dose (mg)# 
Peak Effect, h 
Duration, h 
Short Acting 
Morphine- like 
agonists 
Morphine 
10 IM 
20-60 
PO** 
0.5-1 
1-2 
 
6 
4-7 
 
Hydromorphone 
1.5 IM 
7.5 PO 
0.5-1 
1-2 
4-5 
4-5 
Meperidine 
(pethidine) 
75 IM 
300 PO 
0.5-1 
1-2 
2-4 
3-6 


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SHORT- AND LONG-ACTING OPIOIDS for Moderate to Severe Pain 
Class 
Generic Name 
Dose (mg)# 
Peak Effect, h 
Duration, h 
Oxycodone 
20-30 
PO 
1-2 
3-6 
Oxymorphone 
1 IM 
10 PR 
0.5-1 
1.5-3 
3-6 
4-6 
Agents specifically 
indicated for 
breakthrough 
cancer pain in 
subjects with cancer 
Oral transmucosal 
Fentanyl citrate 
(OTFC) 
800 
mcg 
PO 
0.3- 
0.5 
 
Related to blood 
levels of the 
drug 
Fentanyl buccal 
tablet 
- 
0.5- 
0.75 
- 
Partial agonist 
Buprenorphine 
0.4 IM 
0.5-1 
6-8 
Mixed 
agonists-antagonists 
Butorphanol 
2 IM 
0.5-1 
3-4 
 
Nalbuphine 
10 IM 
0.5-1 
3-6 
 
Pentazocine 
60 IM 
180 PO 
0.5-1 
1-2 
3-6 
3-6 
Long-Acting 
Morphine- 
like agonists 
Fentanyl 
transdermal 
system 
25 
mcg/h 
24-72 
72 
Levorphanol 
2 IM 
4 PO 
0.5-1 
6-8 
Methadone 
10 IM 
20 PO 
0.5- 
1.5 
4-8 
Modified-release 
morphine 
20-30 
PO** 
3-4 
8-24 
Modified-release 
15-20 
3-4 
8-12 


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SHORT- AND LONG-ACTING OPIOIDS for Moderate to Severe Pain 
Class 
Generic Name 
Dose (mg)# 
Peak Effect, h 
Duration, h 
oxycodone 
PO 
Modified-release 
oxymorphone 
10-15 
3-4 
12 
 
ENDNOTES 
* 
Consider using lower than recommended starting dose in the elderly, in subjects on multiple 
drugs, and in those with renal insufficiency (one half to two thirds recommended dose). Doses must 
be individualized. Low initial doses should be titrated upward if tolerated and clinical effect is 
inadequate. Doses can be increased in weekly increments. Studies of NSAIDs in the cancer 
population are meager; thus dosing guidelines are empiric. 
+ 
Although clinical experience suggests that any of the NSAIDs may be analgesic, pain is an 
approved indication only for those drugs noted. 
§ 
At relatively high doses, consider monitoring for adverse effects, e.g., by checking for occult 
fecal blood of for changes in liver function tests, blood urea nitrogen and creatinine assessments, or 
urinalysis. 
II 
Oral dose that provides analgesia equivalent to 650 mg of aspirin. Starting dose may be higher 
or lower, and dose titration is needed after therapy is begun. 
# 
Dose that provides analgesia equivalent to 10 mg of IM morphine. The equianalgesic dose 
should not be interpreted as the starting, standard, or maximum dose, but rather as a guide; 
particularly useful in switching drugs or changing routes of administration. Depending on subject 
characteristics and prior opioid exposure, the starting dose can be lower of higher, and dose 
titration-either upward or downward-is repeatedly necessary in virtually all subjects. 
** 
Extensive survey data suggest that the relative potency of IM to PO morphine of   
1:6 changes to 1:2 or 1:3 with long-term dosing. 
 
LITERATURE: 
Russell K. Portenoy: Three-step analgesic ladder for management of cancer pain; Dept. of Pain 
Medicine and Palliative care, Beth Israel Medical Center, New York, New York 
 

SAP_001.pdf: 
Foresee Pharmaceuticals Co., Ltd 
CONFIDENTIAL 
Statistical Analysis Plan
Protocol No.: FP01C-17-001 
SAP Version: 1.1 
 
SOP-BDM-016-RD-01, Version 05 (30-Mar-2018) 
Page 1 of 34 
AN OPEN-LABEL, SINGLE-ARM STUDY OF THE EFFICACY, 
SAFETY AND PHARMACOKINETIC BEHAVIOR OF 
LEUPROLIDE MESYLATE INJECTABLE SUSPENSION (LMIS 25 
MG) IN SUBJECTS WITH PROSTATE CANCER 
Protocol No.: FP01C-17-001 (NCT03261999)
STATISTICAL ANALYSIS PLAN 
Version: 1.1 
Date: 05-Dec-2018 
Biostatistician: 
Confidentiality Statement 
This document is the property of Foresee Pharmaceuticals Co., Ltd, and may not-in full or part-be passed on, reproduced, distributed 
to any person, or submitted to any regulatory authorities without prior written permission from Foresee Pharmaceuticals Co., Ltd. 




Foresee Pharmaceuticals Co., Ltd 
CONFIDENTIAL 
Statistical Analysis Plan 
    Protocol No.: FP01C-17-001 
SAP Version: 1.1 
 
 
SOP-BDM-016-RD-01, Version 05 (30-Mar-2018) 
Page 3 of 34 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND TERMS.................................................................................... 5 
1. 
INTRODUCTION .............................................................................................................. 8 
2. 
STUDY OBJECTIVE ........................................................................................................ 8 
3. 
STUDY DESIGN ................................................................................................................ 8 
3.1 OVERALL STUDY DESIGN ............................................................................................... 8 
3.2 PRIMARY ENDPOINT ...................................................................................................... 17 
3.3 SECONDARY ENDPOINT ................................................................................................. 17 
3.4 STUDY POPULATION ...................................................................................................... 18 
4. 
GENERAL STATISTICAL ISSUES .............................................................................. 20 
4.1 CONTINUOUS ENDPOINTS .............................................................................................. 20 
4.2 CATEGORICAL ENDPOINTS ............................................................................................ 21 
4.3 TIME-TO-EVENT ENDPOINTS .......................................................................................... 21 
4.4 SAMPLE SIZE ESTIMATION AND POWER .......................................................................... 21 
5. 
DATA HANDLING PROCEDURES .............................................................................. 22 
5.1 CODING SYSTEM ........................................................................................................... 22 
5.2 MISSING DATA HANDLING ............................................................................................ 22 
6. 
ANALYSIS OF STUDY POPULATIONS ..................................................................... 22 
6.1 INTENT-TO-TREAT (ITT) POPULATION ........................................................................... 22 
6.2 PER-PROTOCOL (PP) POPULATION ................................................................................ 22 
6.3 SAFETY POPULATION .................................................................................................... 23 
6.4 ELECTROCARDIOGRAM (ECG) POPULATION ................................................................. 23 
6.5 PHARMACOKINETIC/ELECTROCARDIOGRAM (PK/ECG) POPULATION .......................... 23 
7. 
DISPOSITION OF PATIENTS AND STUDY COMPLETION .................................. 23 
8. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .................... 23 
8.1 TUMOR HISTORY AND MEDICAL HISTORY .................................................................... 23 
9. 
EFFICACY ANALYSIS .................................................................................................. 24 
9.1 PRIMARY EFFICACY VARIABLE ..................................................................................... 24 
9.2 SECONDARY EFFICACY VARIABLES ............................................................................... 26 
9.3 SENSITIVITY ANALYSIS ................................................................................................. 27 
10. 
EXTENT OF EXPOSURE AND DRUG COMPLIANCE ........................................... 28 
11. 
SAFETY ANALYSIS ....................................................................................................... 28 
11.1 ADVERSE EVENTS ....................................................................................................... 28 
11.2 SERIOUS ADVERSE EVENT .......................................................................................... 29 
11.3 LABORATORY EVALUATION ......................................................................................... 29 
11.4 VITAL SIGNS AND PHYSICAL EXAMINATION ................................................................ 30 
11.5 OTHER VARIABLES RELATED TO SAFETY .................................................................... 30 


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12. 
COMPUTER METHODS ............................................................................................... 34 
 


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LIST OF ABBREVIATIONS AND TERMS 
TERM 
DEFINITION 
AE(s) 
Adverse Event(s) 
AIC 
Akaike’s information criteria 
ALT (SGPT) 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
AST (SGOT) 
Aspartate Transaminase 
BDM 
Biostatistics & Data Management 
BLQ 
below the limit of quantitation 
BP 
Blood Pressure 
BT 
Body Temperature 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CRF 
Case Report Form 
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
ENT 
Ear, Nose, and Throat 
ET 
Early Termination 
EOS 
End of Study 
FDA 
Food and Drug Administration 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HDL 
High Density Lipoprotein 
HR 
Heart Rate 
IP 
Investigational Product 
I-PSS 
International Prostate Symptom Score  


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TERM 
DEFINITION 
IS 
Internal Standard 
ITT 
Intent-to Treat 
K 
Potassium 
LC/MS/MS 
Liquid Chromatography-tandem Mass Spectrometry 
LDL 
Low Density Lipoprotein 
LH 
Luteinizing Hormone 
LLOQ 
lower limit of quantitation 
LMIS 
Leuprolide Mesylate Injectable Suspension 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Magnesium 
msec 
milliseconds 
Na 
Sodium 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Partial Response 
PS 
Performance Status 
PSA 
Prostate Specific Antigen 
QTcF 
QT interval corrected by Fridericia’s Formula 
RBC 
Red Blood Cell 
RR 
Respiratory Rate 
SAE(s) 
Serious Adverse Event(s) 
SCr 
Serum Creatinine 
Scrn 
Screening 
SOC 
System Organ Class 
SOP 
Standard Operation Procedure 
TEAE 
Treat emergent adverse event 


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TERM 
DEFINITION 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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1. INTRODUCTION 
This is a multi-national, multi-center, open-label, single-arm and phase III study to determine the 
efficacy, safety, and pharmacokinetic profile of LMIS 25 mg in patients with prostate cancer. 
Approximately 133 subjects will be enrolled in this study. 
 
This statistical analysis plan (SAP) is based on protocol version 1.1, dated 20-Nov-2017. The SAP 
provides details of data handling procedures and statistical analysis methods for efficacy and safety 
evaluations. It also outlines statistical programming specifications for tables, listings and figures, 
and other details on the analyses not provided in the study protocol. It is noted that in case there is 
discrepancy between the SAP and the protocol then the SAP will supersede the protocol. 
This SAP will include efficacy and safety analysis only. The pharmacokinetic (PK) analysis plan is 
not part of this SAP. 
 
2. STUDY OBJECTIVE 
Primary objectives 
The primary objective of this study is to assess the efficacy and safety of LMIS 25 mg for up to 24 
weeks following 2 subcutaneous doses given 12 weeks apart in subjects with prostate cancer 
 
Secondary objectives 
To establish the serum PK profile of leuprolide for LMIS 25 mg in a subset of subjects with prostate 
cancer 
To assess the ECG effects of leuprolide in relationship to plasma concentrations of both leuprolide 
and testosterone 
 
3. STUDY DESIGN 
3.1 Overall Study Design 
This is a multi-national, multi-center, open-label, single-arm study. All subjects will be males with 
prostate cancer judged to be candidates for medical androgen ablation therapy and all will receive 
LMIS 25 mg in an unblinded fashion. Subjects with morning serum testosterone level > 150 ng/dL 
at screening, adequate organ functions, ECOG performance score ≤ 2, and have a life expectancy of 
at least 18 months will be eligible to enter the study. 
The study duration is approximately 24 weeks. Two separate doses of LMIS 25 mg will be given to 
subjects by subcutaneous injection at 12 weeks apart in an unblinded manner. LMIS 25 mg will be 
administered on Day 0 (Visit 2) and Day 84 (Visit 13). At the end of 12 weeks (Day 84), all 


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subjects who have tolerated LMIS 25 mg will be administered the second dose of LMIS 25 mg and 
will be followed for tolerability, safety, efficacy, PK/PD parameters for another 12 weeks (Day 
168/week 24).  
To evaluate the sustained castration testosterone level after two doses of LMIS 25 mg injections, the 
first enrolled 30 subjects are considered as a subset for PK assessment and will be followed for an 
additional 2 weeks (Day 182/week 26) post Day 168 (week 24) to establish the extended 
pharmacokinetic and pharmacodynamics profiles of serum leuprolide and testosterone levels. This 
additional sampling is meant to assess the flexibility of the time period between doses during 
routine use of LMIS 25 mg. 
The efficacy assessments will be performed in both ITT and PP populations. Efficacy assessment 
will include the percentage of subjects reached the castrate levels (≤ 50 ng/dL) of serum 
testosterone on Day 28 (week 4) post the first dosing of LMIS 25 mg, the effect of LMIS 25 mg on 
serum levels of testosterone, PSA, and luteinizing hormone (LH). The acute-on-chronic (surge) 
effect of serum testosterone and LH will also be monitored in all subjects. In addition, the effects of 
LMIS 25 mg on the percentage of subject with PSA relapse and on the percentage of subjects that 
achieves normal serum PSA level will be determined at the end of study. 
Safety assessments will include AE/SAE monitoring. All AEs and SAEs that occur during the study 
period will be recorded in Case Report Forms (CRFs) and followed until resolution or until the 
events are considered stable. In addition, SAEs will be recorded and reported as required by both 
local and international regulatory requirements.  
Additional safety assessments include vital signs, physical examinations, local injection site 
reaction, assessments of bone pain, urinary signs, and symptoms, and laboratory assessments.  
All concomitant medication used during the study period will be recorded in the CRF until the end 
of the study. 
The remaining approximately 103 subjects will have blood samples collected for determining the 
serum leuprolide on Day 0 (prior to the first dose of LMIS 25 mg, and 4 hours post the first dose), 
Days 1, 3, 14, 21, 28, 56, 77, 84 (week12: prior to the second dose and 4 hours post dose), 85, 86, 
87, 98, 112, 140, 161, and 168 (week 24/end of study (EOS)). 
Serum testosterone and LH levels will be determined in all subjects using blood samples collected 
at the specified time points along with serum leuprolide analysis.  
Blood samples for determining the extended PK/PD profile of serum testosterone concentrations 
will be collected in the first enrolled 30 subjects on Day 0 (prior to the first dose of LMIS 25 mg 
and 2 h, 4 h, and 8 h post dose), Days 1, 2, 3, 7, 14, 21, 28, 42, 56, 77, 84 (week 12: prior to the 
second dose and 2 h, 4 h, and 8 h post dose), Days 85, 86, 87, 98, 112, 126, 140, 161, 168 (week 24) 
and Day 182 (week 26). 


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For determining the serum testosterone concentration in the remaining 103 subjects, blood samples 
will be collected on Day 0 (prior to the first dose of LMIS 25 mg and 4 hours post dose), Days 1, 3, 
14, 21, 28, 56, 77, 84 (week 12: prior to the second dose of LMIS 25 mg and 4 hours post dose), 85, 
86, 87, 98, 112, 140, 161, and 168 (week 24/end of study (EOS)). 
Blood samples for determining the serum LH concentrations will be collected on Day 0 (prior to the 
first dose of LMIS 25 mg), Days 1, 2, 3, 7, 14, 21, 28, 42, 56, 77, 84 (week 12, prior to the second 
dose of LMIS 25 mg), 85, 86, 87, 98, 112, 126, 140, 161, 168 (week 24; end of study) in the first 
enrolled 30 subjects. 
For determining the serum LH concentration in the remaining 103 subjects, blood samples will be 
collected on Day 0 (prior to the first dose of LMIS 25 mg), Days 1, 3, 14, 21, 28, 56, 77, 84 (week 
12: prior to the second dose of LMIS 25 mg), 85, 86, 87, 98, 112, 140, 161, and 168 (week 24/end 
of study (EOS)). 
Serum testosterone concentrations will be measured using a validated LC/MS/MS method. The 
method validation follows the European Medicines Agency (EMA) Guideline on Bioanalytical 
Method Validation (EMEA/CHMP/EWP/192217/2009) and the FDA Guidance for Industry: 
Bioanalytical Method Validation, May 2001. 
The measurement of serum LH concentrations will be performed using a validated bioanalytical 
assay following the FDA and ICH guidance..  
For subjects who terminate early or withdraw, phone contacts will be performed at 12 weeks after 
the last injection of the investigational product (IP) to collect information concerning drug-related 
AEs, concomitant medication, non-drug therapy received for AE treatment, disease progression 
status, and subject survival status.


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Table 3.1-1 
Study Schedule Visits 1-13 
 


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Abbreviation: Baseline: Day 0; AE: Adverse Event; BT: Body temperature; ECG: Electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group Scale of Performance Status; 
EOS: end of study; ET: early termination; HbA1c: glycosylated hemoglobin; HR: Heart rate; LH: luteinizing hormone; PD: Pharmacodynamic(s); PK: Pharmacokinetic(s); PSA: 
Prostate Specific Antigen; RR: Respiratory rate; Scrn: Screening. BP: Blood pressure; VAS: Visual Analogue Scale; I-PSS International Prostate Symptom Score  
* If the subject cannot return on Day 84 (the second dose, Visit 13), please have the subsequent visits on Days 85, 86, 87, 98, and 112 to be scheduled according to 
the actual occurred date of the Day 84 visit. For the Day140 Visit (Visit 20), adjust the scheduled date according to the date when the first injection was received. 
# Procedures/ examinations for the first enrolled 30 subjects only. 
1 Cancer/tumor history should be recorded in a life-time basis. 
2 Medical and medication history (including procedural and surgical history, blood donations, and vaccinations) will be recorded up to 6 months prior to screening 
Visit. Concomitant medication use will be recorded up to 6 months prior to screening visit.  


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3 Height will be only measured at screening visit. Weight will be measured at screening, Day 84, and EOS. 
4 Vital signs include BP, HR, RR, and BT. 
5 12-lead ECG monitoring will be performed at specified time points. When 12-lead ECG has to be performed on dosing days, it will be performed prior dosing and 
at 4-hour post LMIS 25 mg injection in all subjects on dosing days (Days 0 and Day 84). 
6 Testosterone samples will be collected in the morning at specified time points as shown in the above schedule. On dosing days (Day 0 and Day 84), blood samples 
for testosterone analysis will be collected before LMIS 25 mg administration. Serum testosterone levels will be analyzed at the QPS Bioanalytical Lab. For fast 
turn-around of assay results, a sample for the screening testosterone will also be sent to the Central Lab. After that, additional samples for testosterone may be 
ordered by the investigator at their discretions and analyzed at the Central Lab using commercial diagnostic assays for fast turn-around of results. 
7 LH samples will be collected in the morning at specified time points as shown in the above schedule. On dosing days (Day 0 and Day 84), blood samples for LH 
analysis will be collected before LMIS 25 mg administration. Serum samples for LH concentrations will be analyzed at the QPS Bioanalytical Lab using a 
validated ELSIA method. More frequent tests of LH may be ordered by the investigators at their discretion, and these samples can be analyzed at the Central Lab 
for a faster data turn-around. Serum samples to the QPS Bioanalytical Lab will be batched and shipped periodically. 
8 Hematology tests include CBC, Hb, Hct, RBC count, WBC count with differential and platelet count. 
9 Biochemistry tests include ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, Mg, Ca and P), blood glucose, and lipid profile (LDL, HDL, 
triglycerides) 
10 Urinalysis tests include pH, specific gravity, leukocyte, erythrocyte, urine glucose, nitrate, and protein. 
Note: Regarding the time window for blood sample collection, at 2, 4, 8 hours post LMIS 25 mg administration on Day 0 (Visit 1) and Day 84 (Visit 
13), a 15-minute time window is allowed; at Visits 6 to 9 (Day 7 to Day 28), a ± 1-day window is allowed. At Visits 10 and 12 (Day 42 to Day 77), a ± 
3-day window is allowed. At Visits 13 to 16 (Day 84, for the second dose injection, week 12, to Day 87), only ± 1-day window is allowed. At Visits 17 
to 21 (Day 98 to Day 161), a ± 3-day window is allowed. At Visits 22 (Day 168), a ± 5-day window is allowed. At Visit 23 (Day 182), a ± 3-day 
window is allowed. 


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Table 3.1-2 
Study Schedule Visits 14-EOS 
 


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Abbreviation: Baseline: Day 0; AE: Adverse Event; BT: Body temperature; ECG: Electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group Scale of Performance Status; 
EOS: end of study; ET: early termination; HbA1c: glycosylated hemoglobin; HR: Heart rate; LH: luteinizing hormone; PD: Pharmacodynamic(s); PK: Pharmacokinetic(s); PSA: 
Prostate Specific Antigen; RR: Respiratory rate; Scrn: Screening. BP: Blood pressure; VAS: Visual Analogue Scale; I-PSS: International Prostate Symptom Score. 
* If the subject cannot return on Day 84 (the second dose, Visit 13), please have the subsequent visits on Days 85, 86, 87, 98, and 112 to be postponed according to 
the actual occurred date of the Day 84 visit. For the Day140 Visit (Visit 20), adjust the scheduled date according to the date when the first injection was received. 
# Procedures/ examinations for the first enrolled 30 subjects only. 
 For early termination subjects (ET), end of study (EOS) procedure and examination should be performed on that day. In addition, phone contacts should be 
performed at 12 weeks after the last injection of investigational product to collect drug-related AE, concomitant medication or non-drug therapy received for AE 
treatment, disease progression status, and subject survival status. 
2 Concomitant medication use will be recorded up to 6 months prior to screening visit. 
3 Height will be only measured at screening visit. Weight will be measured at screening, Day 84 (week 12), and EOS (Week 24). 
4 Vital signs include BP, HR, RR, and BT 
5 12-lead ECG monitoring will be performed at specified time points. 
6 
.Testosterone samples will be collected in the morning at specified time points as shown in the above schedule. Serum testosterone levels will be analyzed at the 
QPS Bioanalytical Lab.  
7 LH samples will be collected in the morning at specified time points as shown in the above schedule. On dosing days (Day 0 and Day 84), blood samples for LH 
analysis will be collected before LMIS 25 mg administration. Serum samples for LH concentrations will be analyzed at the QPS Bioanalytical Lab using a 
validated ELSIA method. More frequent tests of LH may be ordered by the investigators at their discretion, and these samples can be analyzed at the Central Lab 
for a faster data turn-around. Serum samples to the QPS Bioanalytical Lab will be batched and shipped periodically. 
8 Hematology tests include CBC, Hb, Hct, RBC count, WBC count with differential and platelet count. 
9 Biochemistry tests include ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, Mg, Ca and P), blood glucose, and lipid profile (LDL, HDL, 
triglycerides) 


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10 Urinalysis tests include pH, specific gravity, leukocyte, erythrocyte, protein, urine glucose, and nitrate. 
Note: Regarding the time window for blood sample collection, at 2, 4, 8 hours post LMIS 25 mg administration on Day 0 (Visit 1) and Day 84 (Visit 
13), 15-minute time window is allowed; at Visits 6 to 9 (Day 7 to Day 28), a ± 1-day window is allowed. At Visits 10 and 12 (Day 42 to Day 77; week 
6 to week 11), a ± 3-day window is allowed. At Visits 13 to 16 (Day 84 for the second dose injection, week 12 visit, to Day 87), only ± 1-day window 
is allowed. At Visits 17 to 21 (Day 98 to Day 161), a ± 3-day window is allowed. At Visits 22 (Day 168), a ± 5-day window is allowed. At Visit 23 
(Day 182), a ± 3-day window is allowed. 


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3.2 Primary Endpoint 
The primary endpoint of efficacy is to determine the percentage of subjects with a serum 
testosterone concentration suppressed to castrate levels (≤ 50 ng/dL) on Day 28 ± 1 day (week 4) 
following the first injection of LMIS 25 mg, and the proportion of subjects with serum testosterone 
suppression (≤ 50 ng/dL) from Day 28 ± 1 day (week 4) through Day 168 ± 5 days (week 24) until 
the end of the study. 
 
3.3 Secondary Endpoint 
Efficacy:  
• 
The mean acute-on-chronic (surge) changes in testosterone and LH levels from just prior to the 
second injection through 14 days after the second injection of LMIS 25 mg (Days 85-87, week 
13; Day 98 [14 days post the second dose], week 14) 
• 
Effect of LMIS 25 mg on change of serum prostate-specific antigen (PSA) levels  
• 
Effect of LMIS 25 mg on change of serum LH levels  
• 
The percentage of subject with PSA relapse defined as after achieving the serum PSA level ≤ 4 
ng/mL post LMIS 25 mg injection but with an increase in serum PSA of >50% PSA nadir by 
Day 168 (week 24) 
• 
The percentage of subject achieving normal serum PSA level (<4 ng/mL) on Day 168 ± 5 days 
(week 24) 
• 
The percentage of subjects with enhanced serum testosterone concentration suppression to ≤ 20 
ng/dL on Day 28 ± 1 day (week 4) and on Day 168 ± 5 days (week 24) 
Safety:  
• 
Adverse event (AE)/ serious adverse event (SAE) reporting 
• 
Assessment of injection site reaction 
• 
Change in bone pain measurement (by Visual Analogue Scale [VAS] scale) 
• 
Change in urinary signs and symptoms and total scores (by the International Prostate Symptom 
Score, I-PSS sheet) 
• 
Change in vital signs (BP, HR, RR, weight) 
• 
Change in physical examinations with clinical significance compared to baseline by principal 
investigator’s judgment   


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• 
Change in lab data, including liver function (AST, ALT, ALP), renal function (BUN, SCr), 
complete blood count with platelets, clinical chemistries (K, Na, Mg, Ca and P), urinalysis, 
serum glucose, lipid profile (LDL, HDL, triglycerides), and HbA1c level 
• 
Clinically significant changes in 12-lead resting electrocardiogram (ECG) per the investigator’s 
judgment 
• 
Change from baseline in the ECG parameters of QTcF, HR, PR, and QRS 
• 
Change from baseline in the ECG parameters of QTcF, HR, PR, and QRS in relation to the 
serum concentrations of leuprolide and testosterone 
 
3.4 Study Population 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study: 
1. Males aged ≥ 18 years old 
2. Males with histologically confirmed cancer of the prostate 
3. Subjects who are judged by the attending physician and/or principal investigator to be a 
candidate for androgen ablation therapy 
4. Baseline morning serum testosterone level > 150 ng/dL performed at screening visit 
5. Eastern Cooperative Oncology Group (ECOG) Performance score ≤ 2 
6. Life expectancy of at least 18 months 
7. Laboratory values 
 Absolute neutrophil count ≥ 1,500 cells/µL 
 Platelets ≥ 100,000 cells/µL 
 Hemoglobin ≥ 10 gm/dL 
 Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 
 AST (SGOT) ≤ 2.5 × ULN 
 ALT (SGPT) ≤ 2.5 × ULN 
 Serum creatinine ≤ 1.5 mg/dL 
 Lipid profile within acceptable range according to investigator’s opinion 


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 Serum glucose within acceptable range according to investigator’s opinion 
 HbA1c ≤9.5% 
 Clinical chemistries (K, Na, Mg, Ca and P) within acceptable range according to 
investigator’s opinion 
 Normal urinalysis results within: 
 RBCs ≤ 3 RBCs/hpf 
 WBCs ≤ 5 WBCs/hpf   
 Nitrate: negative 
 Glucose: <0.1g/dL; but <1.0 g/dL in subjects with diabetes mellitus  
8. Agree to use male contraceptive methods during study trial 
9. In the investigator’s opinion, the ability to understand the nature of the study and any hazards 
of participation, and to communicate satisfactorily with the investigator and to participate in, 
and to comply with, the requirements of the entire protocol 
10. All aspects of the protocol explained and written informed consent obtained 
Exclusion Criteria 
Subjects presenting with any of the following will not be included in the present study. 
1. Receipt of chemotherapy, immunotherapy, cryotherapy, radiotherapy, or anti-androgen 
therapy concomitantly, or within 8 weeks prior to screening visit, for treatment of Cancer of 
the prostate. Radiation for pain control will be allowed during the study. 
2. Receipt of any vaccination (including influenza) within 4 weeks of screening visit 
3. History of blood donation within 2 months of screening visit 
4. History of anaphylaxis to any LH-RH analogues 
5. Receipt of any LH-RH suppressive therapy within 6 months of screening visit 
6. Patients who were previously enrolled in the LMIS 50 mg study 
7. Major surgery, including any prostatic surgery, within 4 weeks of screening visit 
8. History and concomitant clinical and radiographic evidence of central nervous system/spinal 
cord metastases and subjects at risk for spinal cord compression  
9. Clinical evidence of active urinary tract obstruction and subjects at risk for urinary obstruction 


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10. History of bilateral orchiectomy, adrenalectomy, or hypophysectomy 
11. History or presence of hypogonadism, or receipt of exogenous testosterone supplementation 
within 6 months of screening visit 
12. Clinically significant abnormal ECG and/or history of clinically significant cardiovascular 
disease as judged by the investigator 
13. History of drug and/or alcohol abuse within 6 months of screening visit 
14. Contraindication to leuprolide or an LH-RH agonist as indicated on package labeling 
15. Use of 5-alpha reductase inhibitor within the last 6 months of screening visit 
16. History or presence of insulin-dependent diabetes mellitus (Type I). Presence of well 
controlled diabetes mellitus Type II will be allowed if only oral hypoglycemic are required. 
Prostate cancer subjects with poor controlled diabetes mellitus with Hb1Ac > 9.5% or urine 
glycosuria > 1.0 g/dL should be excluded. 
17. Use of systemic corticosteroids at a dose > 10 mg/d or anti-androgens 
18. Use of any investigational agent within 4 weeks of screening visit 
19. Use of any over-the-counter (OTC) medication within 4 weeks of screening visit except for 
those listed in the permitted Concomitant Treatment section. 
20. Uncontrolled intercurrent illness that would jeopardize the subject’s safety, interfere with the 
objectives of the protocol, or limit the subject’s compliance with study requirements, as 
determined by the investigator in consultation with the sponsor 
 
4. GENERAL STATISTICAL ISSUES 
For data listings, all raw data will be displayed exactly as provided. Partial date(s) will be listed as 
provided in the listings. The partial date(s) will be imputed when using for calculation. For the start 
date, a missing month is supplied a default value of January and a missing day is supplied a default 
value of 1. For the stop date, a missing month is supplied a default value of December and a 
missing day is supplied a default value of the last day of the month. The Baseline is defined as the 
last observation prior to first dose unless otherwise specified. 
 
4.1 Continuous endpoints 
Continuous variables will be summarized and presented as number of observations, mean, standard 
deviation (SD), median, range, Hodges-Lehmann estimator, and 95% CI. Changes from baseline 


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will be tested by paired t-test or Wilcoxon signed-rank (if data violated the normal assumption, i.e. 
the p-value of test of normality is <0.05) test for continuous variables using a significance level of 
0.05. For summaries of quantitative data, the median, minimum and maximum value will be reported 
exactly as the raw data are reported; measures of central tendency (means will be reported as one 
decimal more than the raw data and measure of variance (SD) will be reported as the two decimals 
more than the raw data. 
 
4.2 Categorical endpoints 
Categorical variables will be presented by frequency and percentage. 
 
4.3 Time-to-event endpoints 
The time-to-event endpoint, percentage of subjects with testosterone suppression (≤ 50 ng/dL) from 
Day 28 (week 4) through Day 168 ± 5 days (week 24) will be analyzed by Kaplan-Meier method. 
The event is defined as as occurring in subjects with a testosterone level > 50 ng/dL between Day 
28 (week 4) and Day 168 (week 24), and it will be presented as number of subjects with event 
(event number), percentage of subjects with event, suppression rate by day 168 along with 95% 
confidence interval, mean, median and 95% confidence interval for median. Some situations are 
noted for efficacy analysis by Kaplan-Meier method: 
1. The subject has an event and it will be analyzed as an event on the day of first testosterone 
escape. 
2. The subject with more than one missing testosterone value will be censored on day of last 
measurement. 
3. Any subject having more than one missing testosterone values will be censored on the day of last 
measurement before the first missing testosterone measurement. 
4.  If subject does not have serum testosterone suppression to castrate level (i.e. serum testosterone 
levels > 50 ng/dL) by Day 28 (week 4), the event date will be set as Day 28 for the analysis of 
percentage of subjects with testosterone suppression (≤ 50 ng/dL) from Day 28 (week 4) 
through Day 168 (week 24). 
 
4.4 Sample size estimation and power 
Approximately 133 subjects are expected to be enrolled in this study. A sample size of 120 will 
achieve 85% power to detect a difference (P1-P0) of 0.0700 by using a one-sided binomial test. The 


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target significance level is 0.0250. This assumes that the population proportion under the null 
hypothesis is 0.9000 and under the alternative to be 0.97. The estimated drop-out rate is 10%, so 
approximately 13 subjects may drop out from the study before Day 168 (week 24). 
Currently, there are totally 144 subjects enrolled in this study. 
 
5. DATA HANDLING PROCEDURES 
5.1 Coding System 
All AEs will be coded according to the MedDRA dictionary, version 21.0 or higher, and be reported 
by System Organ Class and Preferred Term. 
Concomitant medications will be coded according to the World Health Organization (WHO) Drug 
Dictionary. 
 
5.2 Missing Data Handling 
For missing data related to a safety or efficacy endpoints, no missing data imputation method will 
be performed unless otherwise specified.  
 
6. ANALYSIS OF STUDY POPULATIONS 
In this study, there will be five populations, including intention-to treat (ITT), per protocol (PP), 
safety, ECG, and PK/ECG populations. The ITT and PP populations will be used for the efficacy 
analysis. The safety population will only be used for the safety analysis. The ECG and PK/ECG 
populations will be used for the ECG analysis. The populations for analysis applied in this study are 
defined as follows: 
 
6.1 Intent-to-treat (ITT) Population  
The Intention-To-Treat (ITT) population will consist of any subject receiving at least one dose of 
LMIS 25 mg. 
 
6.2 Per-protocol (PP) Population 
The Per Protocol (PP) population will be composed of those subjects who received 2 doses of LMIS 
25 mg without major deviations that will impact the assessment of the primary efficacy endpoint. 


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6.3 Safety Population 
The safety population will consist of any subject receiving a dose of LMIS 25 mg.    
 
6.4 Electrocardiogram (ECG) Population  
The ECG population will consist of any subject receiving at least one dose of LMIS 25 mg and who 
had an ECG value measured for at least 1 post dose time point. 
 
6.5 Pharmacokinetic/Electrocardiogram (PK/ECG) Population  
The PK/ECG population will consist of any subject in the ECG population with post dose 
time-matched serum concentrations of leuprolide or testosterone. 
 
The analysis of study population will be summarized in Table 14.1.1. Besides, subjects excluded 
from the analysis will be listed in Listing 16.2.3. 
 
7. DISPOSITION OF PATIENTS AND STUDY COMPLETION 
Data on the study completion status and primary reason for study discontinuation will be listed in 
Listing 16.2.1. All subjects’ disposition and completion status will be summarized in Table 14.1.1. 
Individual subject eligibility will be listed in Listing 16.2.2.1. All protocol deviation(s) will be listed 
in Listing 16.2.2.2. 
  
8. DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics information (Age (years), Gender, Race and Ethnicity) will be listed in Listing 
16.2.4.1. Demographics information and baseline characteristics included: Age (years), Gender, 
Race, Ethnicity, Diagnosis (days) of prostate carcinoma history, each TNM of prostate carcinoma 
history and ECOG performance will be summarized in Table 14.1.2. 
 
8.1 Tumor History and Medical History 
Medical history and concurrent medical conditions data will be listed by subject as following: 
Listing 16.2.4.2: Tumor History 
Listing 16.2.4.3: Other Tumor History 
Listing 16.2.4.4: Previous Treatment of Malignant Disease 
Listing 16.2.4.5: Medical/ Surgery History 


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Listing 16.2.4.6: Previous Blood Donation 
 
9. EFFICACY ANALYSIS 
9.1 Primary Efficacy Variable 
The primary endpoint of efficacy is to determine the percentage of subjects with a serum testosterone 
concentration suppressed to castrate levels (≤ 50 ng/dL) on Day 28 ± 1 day (week 4) following the 
first injection of LMIS 25 mg and to determine the proportion of subjects with serum testosterone 
suppression (≤ 50 ng/dL) from Day 28 ± 1 day (week 4) through Day 168± 5 days (week 24) until the 
end of the study. 
The percentage of subjects with a serum testosterone concentration suppressed to castrate levels (≤ 
50 ng/dL) on Day 28 ± 1 day (week 4) and on Day 168± 5 days (week 24) will be analyzed using a 
standard large sample normal approximation to a Binomial distribution and it will be summarized as 
count, percentage and exact 95% CI for binomial proportion. 
The percentage of subjects with testosterone suppression (≤ 50 ng/dL) from Day 28 (week 4) 
through Day 168 ± 5 days (week 24) will be analyzed using the Kaplan-Meier approach. In this 
analysis an event is defined as occurring in subjects with a testosterone level > 50 ng/dL between 
Day 28 (week 4) and Day 168 (week 24). To accommodate drop-out and missing values the 
following censoring rules will be observed: 
Table 9.1-1 
Data Censoring Rules 
Subject 
Discontinued 
Day 28- 168 or Day of 
Discontinuation 
To Be Handled As 
More Than 1 
Missing 
Testosterone 
Value 
Any Escape* 
Yes 
No 
No 
Censored on day of last measurement 
Yes 
No 
Yes 
Event on day of first escape 
Yes 
Yes 
No 
Censored on day of last measurement before 
the first missing 


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Yes 
Yes 
Yes 
Event on day of first escape 
No 
No 
No 
Censored on Day 168 
No 
No 
Yes 
Event on day of first escape 
No 
Yes 
No 
Censored on day of last measurement before 
the first missing 
No 
Yes 
Yes 
Event on day of first escape 
No suppression by Day 28 
Event on Day 28 
*The escape (event) is defined as subject with a testosterone level >50 ng/dL 
 
The testosterone level will be listed by subject and visit in Listing 16.2.6.1.  
The duration of time to reach a serum testosterone of >50 ng/dL is calculated from Day 28 to Day 
168 or Day of Discontinuation. The duration of time to reach a serum testosterone of >50 ng/dL 
will be summarized and presented as number of subjects with event (event number), percentage of 
subjects with event, suppression rate by day 168 along with 95% confidence interval, mean, median 
and 95% confidence interval for median. A positive outcome to the study will be achieved if the 
lower 95% confidence interval bound for the response rate at Day 168 is greater than 90%. 
Subjects exhibiting post-suppression breakthrough of serum testosterone to >50 ng/dL will also be 
summarized based on a subset for subjects who reach castration on day 28. The calculation formula 
is: [The subjects exhibiting post-suppression excursions of serum testosterone to >50 ng/dL at 
specific visit] / [The total number of subjects who reach castration at day 28 and has nonmissing 
serum testosterone value at specific visit] x 100%. It will be summarized as count, percentage and 
exact 95% CI for binomial proportion. 
The summary of primary efficacy analysis will be presented as following:  
Table 14.2.1: Summary of Subjects with a Serum Testosterone Concentration Suppressed to 
Castrate Levels (ITT Population) 
Table 14.2.2: Summary of Subjects with Serum Testosterone Suppression Maintained from Day 28 
through Day 168 (ITT Population) 
Table 14.2.3: Summary of Subjects Exhibiting Post-Suppression Breakthrough of Serum 
Testosterone to >50 ng/dL (ITT Population) 


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Table 14.2.13: Summary of Subjects with a Serum Testosterone Concentration Suppressed to 
Castrate Levels (PP Population) 
Table 14.2.14: Summary of Subjects with Serum Testosterone Suppression Maintained from Day 
28 through Day 168 (PP Population) 
Table 14.2.15: Summary of Subjects Exhibiting Post-Suppression Breakthrough of Serum 
Testosterone to >50 ng/dL (PP Population) 
Also, the Kaplan-Meier curve for duration of time to reach a serum testosterone of >50 ng/dL will 
be presented in Figure 14.2.1 and Figure 14.2.2 for ITT and PP populations. 
 
9.2 Secondary Efficacy Variables 
The analyses of secondary endpoints will be based on the following 
• 
The mean acute-on-chronic (surge) changes in testosterone and LH levels from just prior to the 
second injection through 14 days after the second injection of LMIS 25 mg (Days 85-87, week 
13; Day 98 [14 days post the second dose], week 14)  
An 'acute-on-chronic' change is defined as a >25% increase in testosterone and LH levels compared 
to the testosterone and LH levels just prior to the second injection. The mean acute-on-chronic 
(surge) changes in testosterone and LH levels will be analyzed based on subset of subjects have an 
'acute-on-chronic' change at Visit 14 (Day 85), Visit 15 (Day 86), Visit 16 (Day 87) and Visit 17 
(Day 98). The mean acute-on-chronic (surge) changes in testosterone and LH levels from just prior 
to the second injection through 14 days after the second injection of LMIS 25 mg (Day 98, week 14) 
will be summarized descriptively and a paired t-test or Wilcoxon signed-rank test will be used 
under significance level of 0.05. The summary results will be provided as Table 14.2.4~Table 
14.2.5 for ITT population and Table 14.2.16~Table 14.2.17 for PP population. 
• 
Effect of LMIS 25 mg on change of serum prostate-specific antigen (PSA) levels  
• 
Effect of LMIS 25 mg on change of serum LH levels 
The serum PSA levels and serum LH levels will be listed by subject in Listing 16.2.6.2 and Listing 
16.2.6.3. The change from baseline for serum PSA levels at scheduled visit and serum LH levels at 
scheduled visit will be summarized descriptively and a paired t-test or Wilcoxon signed-rank test 
will be used with significance level of 0.05. The summary results will be provided as Table 
14.2.6~Table 14.2.7 and Table 14.2.18~Table 14.2.19 for ITT and PP populations. Also, the PSA 
levels over time will be presented in Figure 14.2.5~Figure 14.2.6 for ITT and PP populations; the 
LH levels over time will be presented as Figure 14.2.3~Figure 14.2.4 for ITT and PP populations. 


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• 
The percentage of subject with PSA relapse defined as after achieving the serum PSA level ≤ 4 
ng/mL post LMIS 25 mg injection but with an increase in serum PSA of >50% PSA nadir by 
Day 168 (week 24) 
• 
The percentage of subject achieving normal serum PSA level (<4 ng/mL) on Day 168 ± 5 days 
(week 24) 
The subject with PSA relapse is defined as after achieving the serum PSA level ≤ 4 ng/mL post 
LMIS 25 mg injection but with an increase in serum PSA of >50% PSA nadir by Day 168 (week 
24), i.e. subject achieves the serum PSA level ≤ 4 ng/mL on Day 28 but with an increase in serum 
PSA of >50% PSA on Day 84 or Day 168, or subject achieves the serum PSA level ≤ 4 ng/mL on 
Day 84 but with an increase in serum PSA of >50% PSA on Day 168.  
The incidence of PSA relapse will be presented as subject count, percentage, and exact 95% CI for 
binomial proportion in Table 14.2.8 and Table 14.2.20 for ITT and PP populations; and the 
percentage of subject achieves normal serum PSA level will be presented as Table 14.2.9 and Table 
14.2.21 for ITT and PP populations. Besides, the additional analyses of PSA levels <4 ng/mL for 
subjects with elevated PSA at baseline as Table 14.2.11 and Table 14.2.23. It is noted that the 
normal serum PSA level shall be analyzed as <4 ng/mL rather than <4 ng/dL since it is typo on 
protocol. 
• 
The percentage of subjects with enhanced serum testosterone concentration suppression to ≤ 
20 ng/dL on Day 28 ± 1 day (week 4) and on Day 168 ± 5 days (week 24) 
The percentage of subjects with a serum testosterone ≤ 20 ng/dL on Day 28 ± 1 day (week 4) and 
on Day 168 ± 5 days (week 24) will be analyzed using a standard large sample normal 
approximation to a Binomial distribution. The summary results included subject count, percentage 
and exact 95% CI for binomial proportion will be presented as Table 14.2.10 and Table 14.2.22 for 
ITT and PP populations. 
Based on protocol, the testosterone level is assessed at Week 26 for the first enrolled 30 subjects. 
The additional analysis of subjects with a serum testosterone concentration suppressed to castrate 
levels (<= 50 ng/dL) at Week 26 will be presented as Table 14.2.12 and Table 14.2.24 for ITT and 
PP populations. 
 
9.3 Sensitivity Analysis 
The sensitivity analysis for primary efficacy endpoint will be performed by excluding all subjects 
from site CZ03 due to GCP compliance issues at this site. These subjects will be excluded from 


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both ITT and PP populations as another analysis scenario (ITT excluding subjects from site CZ03, 
and PP excluding subjects from site CZ03) for sensitivity analysis.  
The summary results will be presented as Table 14.2.25~Table 14.2.26 and Table 14.2.27~Table 
14.2.28 for ITT and PP populations. 
 
10. EXTENT OF EXPOSURE AND DRUG COMPLIANCE 
The study treatment LMIS 25 mg will be administered on Day 0 (Visit 2) and Day 84 (Visit 13; 
week 12). The study treatment date, time will be listed by subject in Listing 16.2.5.1. The 
proportion of subjects received first and second administration will be provided as Table 14.1.1. 
 
11. SAFETY ANALYSIS 
11.1 Adverse Events 
All AEs will be coded by system organ class and preferred term for analysis. Treatment-emergent 
adverse event (TEAE) is defined as AEs occur after the first administration of study drug, or AEs 
occur before the first administration of study drug and worsen in severity after first dose. Unless 
otherwise specified, all adverse event summaries will include the TEAEs only. For purposes of the 
summary tables, AEs will be classified as either related or not related to study drug. The 
drug-related AEs are assessed as ‘Definite’, or ‘Possible’ related to study treatment. If the 
relationship is missing, the AE will also be assessed as drug-related AE. This summary will present 
the number and percentage of subjects, as well as number of events. For subject with the same AE 
but multiple different severity/relationship (which resolution date=onset date or resolution 
date=onset date+1, except they have different AE No), the multiple event will be combined as one 
AE with the maximum severity/ relationship category for analysis. 
A general summary includes number of events, number and percentage of subjects reporting 
adverse events of all TEAEs will be provided in Table 14.3.1.1.1 according to the following 
categories: 
• 
Subject with any TEAE 
• 
Subject with any drug-related TEAE 
Also, a general summary of all TEAEs will be provided in Table 14.3.1.1.2 according to the 
following categories: 
• 
TEAEs by severity 
• 
TEAEs by relationship
  
• 
Serious TEAEs 


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• 
Drug-related TEAEs by severity 
 
Other summary tables for adverse events will be summarized by MedDRA system organ class and 
preferred term include: 
Table 14.3.1.2: Treatment-Emergent Adverse Events - MedDRA 
Table 14.3.1.3: Treatment-Emergent Adverse Events by Severity - MedDRA 
Table 14.3.1.4: Treatment-Emergent Adverse Events by Relationship to Study Drug - MedDRA 
Table 14.3.1.5: Treatment-Emergent Adverse Events for Grade ≥3 – MedDRA 
Table 14.3.1.6: Drug-Related Treatment-Emergent Adverse Events by Severity – MedDRA 
Table 14.3.1.9: Treatment-Emergent Adverse Events - MedDRA (Preferred Term over XX %) 
The listing of all AEs will be provided in Listing 16.2.7.1. In addition, TEAEs leading to study 
discontinuation will be provided in Listing 16.2.7.2.  
 
11.2 Serious Adverse Event 
The summary of SAEs will be presented by MedDRA system organ class and preferred term, and this 
summary will present the number and percentage of subjects, as well as number of events: 
Table 14.3.1.7: Treatment-Emergent Serious Adverse Events - MedDRA 
Table 14.3.1.8: Treatment-Emergent Serious Adverse Events by Relationship to Study Drug - 
MedDRA 
A listing of all serious adverse events will be provided in Listing 16.2.7.3. 
 
11.3 Laboratory Evaluation  
Clinical laboratory tests included hematology, biochemistry and urinalysis. 
Hematology tests include complete blood count (CBC), Hb, Hct, RBC count, WBC count, WBC 
differential (neutrophils, eosinophils, basophils, lymphocytes, and monocytes), platelet count, and 
HbA1c.  
Biochemistry tests include ALT, AST, ALP, total bilirubin, BUN, Serum Cr, electrolytes (K, Na, Mg, 
Ca and P), blood glucose, and lipid profile (LDL, HDL, triglycerides) 
Urinalysis tests include pH, specific gravity, leukocyte, erythrocyte, urine glucose, nitrate, and 
protein.. 
By-subject-visit listings of measured values for clinical laboratory test data (hematology, 
biochemistry and urinalysis) will be prepared in Listing 16.2.8.1 ~ Listing 16.2.8.3. Observations 
outside the normal range will be flagged. The abnormal values will be flagged with ‘L’ (low) for 


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values below the lower limit of the laboratory’s normal range, ‘H’ (high) for values above the upper 
limit of the laboratory’s normal range or ‘A’ for values out of the laboratory’s normal range. The 
abnormal values for clinical laboratory test data (hematology, biochemistry and urinalysis) will be 
prepared in Table 14.3.4. The record with observed value of clinical laboratory data below or above 
the detection limit will be imputed with the detection limit for analysis.  
The baseline is defined as the last observation prior to first dose unless otherwise specified. The 
summary results of laboratory data (hematology, biochemistry and urinalysis) at baseline, EOS/ET 
Visit and change from baseline to the EOS/ET Visit  will be summarized by descriptive statistics and 
paired t-test or Wilcoxon signed- rank test with significance level at 0.05. Results will be presented in 
Table 14.3.5.1~Table 14.3.5.3. The transition matrix of change in laboratory data (normal, abnormal 
NCS and abnormal CS status) between baseline and the EOS/ET Visit will be summarized as Table 
14.3.5.4~Table 14.3.5.6. 
 
11.4 Vital Signs and Physical Examination 
Vital Signs 
Individual subject vital signs (height, weight, body pressure, heart rate, respiration rate and body 
temperature) will be listed in Listing 16.4.1. 
The baseline is defined as the last observation prior to first dose unless otherwise specified. The 
summary results of vital signs (body pressure, heart rate, respiration rate and body temperature) and 
weight at baseline, EOS/ET Visit, and the change from baseline will be summarized descriptively. 
Also the change from baseline to the EOS/ET Visit will be tested by paired t-test or Wilcoxon 
signed-rank test at a significance level of 0.05 in Table 14.3.6. 
 
Physical Examination 
Physical examination data (included: General appearance, Skin, Eyes, Ear/ Nose/ Throat (ENT), 
Head, Neck, Heart, Chest, Lungs, Abdomen, Extremities, Lymph nodes, Musculoskeletal and 
Neurological) will be listed in Listing 16.4.2, and will be summarized descriptively as count and 
percentage in Table 14.3.7.1. The transition matrix of physical examination (normal, abnormal NCS 
and abnormal CS status) will be summarized in Table 14.3.7.2. 
 
11.5 Other Variables Related to Safety 
Concomitant Medication and Non-Drug Therapy 
Individual subject concomitant medication and non-drug therapy will be listed in Listing 16.2.5.2. 


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12-Lead ECG 
Individual subject 12-Lead ECG data (heart rate, PR interval, RR interval, QRS duration, QT, QTc 
and overall interpretation) will be listed in Listing 16.4.3.  
The baseline is defined as the last observation prior to first dose unless otherwise specified. The 
summary results of 12-lead resting ECG at baseline, EOS/ET Visit will be summarized 
descriptively in Table 14.3.8.1. The transition matrix for ECGs overall interpretation (normal, 
abnormal NCS and abnormal CS status) will be summarized in Table 14.3.8.2. 
 
Additional 12-Lead ECG and PK Analyses for ECG Report 
A separate ECG report will be provided with the results of the analyses in this section. 
The following corrected QT interval for each visit and time point will be derived and considered the 
primary ECG assessment for the analysis in the ECG report. 
QTcF: The QT interval in units of milliseconds (msec) corrected by the Fridericia formula will be 
calculated as follows: 
, where RR interval will be expressed in units of seconds. 
Descriptive statistics (number of subjects, mean, SD, 2-sided CI [90% for the QTcF interval or 95% 
for other parameters], median, 25th percentile, 75th percentile, minimum, and maximum) will be 
provided for baseline and each visit and time point post dose for results and change from baseline, 
denoted as ΔECG (i.e. ΔQTcF, ΔHR, ΔPR, ΔQRS), for the ECG population. Missing data will not be 
imputed. Unscheduled data will not be summarized or included in analyses. The means and 90% (in 
the case of ΔQTcF) or 95% CIs for the ΔHR, ΔPR, and ΔQRS values, will be displayed graphically 
by scheduled day and time point.  
An analysis will be provided for the PK/ECG population based on a linear mixed effects model. The 
mixed-effects model will contain ΔQTcF as the dependent variable and include the corresponding 
leuprolide or testosterone serum concentrations in separate models with a random intercept and 
slope, day/time point as a categorical variable, and baseline QTcF (adjusted for the overall mean of 
subjects’ baseline data included in the model) as the independent variables. The mixed effects 
model will be used to estimate, for all subjects in the PK/ECG analysis population, the predicted 
population mean ΔQTcF and its corresponding 2-sided 90% CI at mean Cmax of the serum 
concentrations. Serum concentration values reported as below the limit of quantitation (BLQ) will 
be assigned a value of zero in this analysis. This analysis will be repeated for ΔHR, ΔPR, and ΔQRS, 
but 95% CIs will be presented rather than 90%. 
3 (RR)
QT
 
  
QTcF 


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The adequacy of the linear assumption between ΔECG interval and serum concentrations will be 
determined by adding a quadratic term to the mixed-effects model. If the quadratic term is different 
than zero, having a p-value <0.05, and an Akaike's information criteria (AIC) that is smaller in 
comparison to the linear model’s AIC, then a quadratic term may be added. In addition, a 
transformation of the concentrations [e.g. log(Concentration/LLOQ), where LLOQ is the lower 
limit of quantitation of the assay and all values below the LLOQ are replaced with the LLOQ] may 
also be assessed. The best model fit will be determined by the lowest AIC, unless the model results 
are not clinically or physiologically sensible. 
If convergence cannot be reached, adjustment to the model as follows will be considered: the 
random slope may be removed, an alternative covariance structure attempted, or as a last resort, the 
removal of the time effect may be considered. 
The relevant SAS code statements are:  
PROC MIXED DATA = DATA METHOD=REML; 
   CLASS SUBJID ATPTN; 
   MODEL CHG = CONC ATPTN BASEADJ /NOINT SOLUTION OUTP=PRED; 
   RANDOM INTERCEPT CONC /TYPE=UN SUBJECT=SUBJID; 
   ESTIMATE 'ΔECG at Cmax' CONC xx.x / CL ALPHA=0.1; 
RUN; 
In the above statements: 
 CHG represents the ΔQTcF value (or corresponding secondary parameter); 
 CONC represents measured serum concentrations of leuprolide or testosterone; 
 ATPTN represents the day/time point; 
 BASEADJ represents the numeric baseline minus the overall mean of all baseline values for 
the ECG parameter; 
 TYPE=UN means that an unstructured covariance matrix will be used for the correlated 
random effects (INTERCEPT and CONC); 
 xx.x in the ESTIMATE statement represents the estimated arithmetic mean Cmax for 
leuprolide or testosterone. 
Categorical Analyses for ECG Report 
Categorical analyses of HR, PR, QRS, and QTcF will be performed to determine the number and 
percentage of subjects, who meet each of the following criteria at each day/time point and at the 
maximum/minimum QTcF (HR, PR or QRS) value postdose: 
 Result QTcF ≤450, >450 and ≤480, >480 and ≤500, and >500 msec;  


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 Change from baseline ΔQTcF ≤ 30, >30 and ≤60, and >60 msec;  
 PR Outliers (PR >200 msec and a 25% or greater increase from baseline); 
 QRS Outliers (QRS >100 msec and a 25% or greater increase from baseline); 
 HR Outliers (HR <50 beats/min and a 25% or greater decrease from baseline); 
 HR Outliers (HR >100 beats/min and a 25% or greater increase from baseline).  
 
Morphological ECG Diagnostic Statement Analyses for ECG Report 
Abnormal morphological diagnostic statements will be tallied and tabulated for each day/time point 
and overall. The incidence rate of abnormal diagnostic statements will be tabulated for both 
baseline and post dose assessments, and also tabulated with abnormal diagnostic statements 
categorized as treatment emergent diagnostic statements (i.e., abnormal diagnostic statements not 
present on the baseline assessments). The variety of morphology statements with the same meaning 
will be aggregated into defined categories by the Cardiac Safety Expert and incorporated into the 
analysis dataset. For example, T-wave inversion in Lead V2 and T wave flattening in Lead II will 
both be categorized as nonspecific T-wave abnormality. 
Adequacy of HR Correction for ECG Report 
The adequacy of the correction formula for QTcF will be assessed by determining the linear 
relationship of QTcF interval to RR. Adequacy will be defined as a population QTcF:RR slope of 
< |0.045|, and a slope of < |0.045| in at least 50% of individual subjects. If QTcF interval is 
determined to be an inadequate correction, the QT interval with a study specific QTcSS will be 
calculated. 
 
ECOG Performance Status 
Individual subject ECOG performance status will be listed in Listing 16.4.4. The ECOG 
performance status will be summarized descriptively as Table 14.1.2. 
 
Local Injection Site Reaction 
Individual subject Local Injection Site Reaction will be listed in Listing 16.4.5. The local injection 
site reaction as recorded by Grade 0 (None), Grade 1 (Mild), Grade 2 (Moderate) and Grade 3 
(Severe) will be summarized descriptively as count and percentage as Table 14.3.9. 
 
Bone pain and urinary sign and symptoms (I-PSS) 
Individual subject Bone pain and urinary sign and symptoms will be listed in Listing 16.4.6~ Listing 
16.4.8. The summary results of VAS scale for bone pain measurement at baseline, EOS/ET Visit 


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and the change from baseline will be summarized descriptively in Table 14.3.10.1. Also, the change 
from baseline to EOS/ET visit will be tested by paired t-test or Wilcoxon signed-rank test at a 
significance level of 0.05. The urinary sign and symptoms at baseline and EOS/ET Visit will be 
summarized descriptively as Table 14.3.10.1. The transition status for urinary sign and symptoms 
by each scale* will be presented as Table 14.3.10.2. The quality of life will be presented as Table 
14.3.10.3. 
*For Urinary signs and symptoms Q1-Q6: 0 - None, 1 - Less than 1 time in 5, 2 - Less than half the 
time, 3 - About half the time, 4 - More than half the time, and 5 - Almost always. 
For Urinary signs and symptoms Q7: 0 - None, 1 - 1 time, 2 - 2 times, 3 - 3 times, 4 - 4 times, 5 - 5 
or more times. 
For Urinary signs and symptoms quality of life: 0 - Delighted, 1 - Pleased, 2 - Mostly Satisfied, 3 - 
Mixed, 4 - Mostly Dissatisfied, 5 - Unhappy, 6 - Terrible 
 
Unscheduled Assessments 
The unscheduled assessment will be listed in Listing 16.4.9. 
 
Telephone Contact 
The telephone contact information will be listed in Listing 16.4.10. 
  
12. 
COMPUTER METHODS 
All statistical analyses will be conducted using SAS® software, Version 9.3 of the SAS System for 
Windows 7. Copyright© 2013 SAS Institute Inc. SAS and all other SAS Institute Inc. product or 
service names are registered trademarks or trademarks of SAS Institute Inc., Cary
, NC, USA.