A9_-_Sample_TORFP_2_SOW_-_SAD_Study_080624.pdf

Sample Task Order #2 - Statement of Work

NOTE: The following sample Task Orders indicated in this attachment are provided to assess the offeror’s capabilities to conduct and fulfill the requirements of the Statement of Work for clinical trials of similar scope and size to be issued under Task Orders awarded in response to this solicitation. These sample Task Orders will NOT be executed nor will awards be issued for the sample work. Offerors are to include in their proposals a response that specifies the methods by which each sample Task Order will be fulfilled with associated costs.

Single Ascending Dose (SAD) Study

1. Scope

The scope of activities includes all tasks and activities associated with the execution of the requested Phase I trial described herein. The development and finalization for the clinical protocol entitled: A Phase I randomized double-blind placebo-controlled study to assess the safety, tolerability, and pharmacokinetics of BPN-XXXXX following single ascending dose administration to healthy volunteers including but not limited to the development and finalization of study design elements, safety assessments, PK assessments and other protocol requirements performed by the Contractor.

Note: The offerors are to provide a technical proposal including timelines and cost estimate for the execution of above referenced protocol. For the purposes of proposal preparations, assume that the Contractor is tasked with designing a Phase I single ascending dose clinical trial to evaluate the safety profile and PK of BPN-XXXXX, a novel neurotherapeutic in healthy adult volunteers. Objectives of the protocol are a) characterize the systemic safety profile of BPN-XXXXX in a single ascending dose trial and b) characterize the PK of BPN-XXXXX across the range of doses. The design is a randomized double-blind placebo-controlled first-in-human clinical trial. All appropriate non-clinical studies, including the Investigational New Drug (IND)-enabling repeat-dose, Good Laboratory Practice (GLP) toxicology studies have been conducted. Significant safety issues were identified at doses 10-fold above the No- Observed-Adverse-Effect Level (NOAEL) in each of these studies. BPN-XXXXX has a NOAEL of 1000 mg/kg/day in the most sensitive animal species tested (rats). Following multiple doses, changes in hematology were revealed. BPN-XXXXX is well absorbed orally and has an elimination half-life of approximately 8 hours in the rat.

2. Technical Requirements

Independently and not as an agent of the Government, the Contractor shall furnish all necessary services, qualified personnel, materials, equipment, and facilities not otherwise provided by the Government as needed to conduct the clinical trials as described in the Statement of Work.

In addition to the specific technical requirements specified below, the Contractor shall fulfill the general technical requirements defined in the Parent Statement of Work, which shall be considered general technical requirements for all clinical project task orders that are issued.

Clinical project task orders will consist of two components: Base Requirement (Protocol Development and Trial Preparation) and a Quantity Option (Clinical Trial Implementation).

Note: Please reference the SAD Draft Protocol Synopsis for the purposes of preparing the technical proposal. A separate cost proposal estimate must be provided for the Base Requirement and the Quantity Option.

Specifically, the Contractor shall perform all activities as outlined below:

A. Base Requirement: Protocol Development and Trial Preparation

This includes all items and activities that are listed under Specific Technical Requirements for “Protocol Development and Trial Preparation.”

B. Quantity Option: Clinical Trial Implementation This includes all items and activities that are listed under Specific Technical Requirements for “Trial Implementation.”

SAD DRAFT PROTOCOL SYNOPSIS

Study Title A Phase I randomized double-blind placebo-controlled study to assess the safety, tolerability, and pharmacokinetics of BPN-XXXXX following single ascending dose administration to healthy volunteers

Study Number TBD Study Phase Phase I, First in Human Subject Population

Healthy Volunteers

Objectives 1. Characterize the systemic safety of single ascending doses of BPN-XXXXX

2. Characterize the pharmacokinetics (PK) of single ascending doses of BPN-

XXXXX

Study Design and Duration

This is a randomized, double-blind, placebo-controlled, ascending dose study. There will be 6 dose levels, each administered to a cohort of 6 subjects. In addition, each cohort will include 2 subjects administered placebo. This study will employ sentinel dosing, whereby only 2 subjects (1 active + 1 placebo) will be dosed in a blinded manner at the start of a cohort and their safety will be monitored for 24 hours before dosing the rest of the cohort. Consistent with NINDS policies, efforts should be made to enroll males and females and include diverse races and ethnicity.

All subjects will participate in a Screening period lasting up to 28 days, during which they will be assessed for eligibility.

All cohorts will reside in the research unit from Day -1 through Day 3. On Day -1 baseline safety data will be obtained. Subjects will receive a single oral dose on the morning of Day 1. Safety and PK will be obtained through Day 3, and then subjects will be discharged from the unit. Subjects return for an outpatient visit on Day 4. A phone call to ask about adverse events and concomitant medications will take place to all subjects on Day 6. All subjects will return for the final outpatient visit on Day

8. Specifics regarding safety and PK collection are described in the following sections and presented in tabular form in Tables 1 and 2.

Escalation and Stopping Rules

Determination of whether to escalate to the next dose level will be made by a Safety Review Committee (SRC), consisting of a Contractor-provided Independent Safety Monitor, the Principal Investigator, and the Sponsor-provided representative. Dose Limiting Toxicities (DLTs) will be defined as related serious adverse events and related Grade 3 or higher adverse events (grades will be determined using NCI- CTCAE). Safety data will be reviewed for each cohort through the final clinic visit.

The stopping rules are occurrence of a DLT in ≥ 2 subjects. If the stopping rules are triggered, the SRC may make one of the following recommendations: 1) declare the prior tolerated dose level as the maximal tolerated dose (MTD); 2) recommend testing of an intermediate dose level; 3) recommend protocol amendment to increase subject safety; 4) discontinue enrollment and/or the study.

Inclusion and Exclusion Criteria

Each subject must meet the following criteria to be enrolled in this study.

1. Males and females ages 21 through 65 years, inclusive

2. Able to give signed informed consent

3. Able to remain domiciled in research unit for specified periods without interruption

4. a. Eligible female subjects will be:

• non-pregnant

• non-lactating

• surgically sterile or postmenopausal,

b. Eligible male subjects will either be:

• Surgically sterile (i.e., vasectomy), for at least 3 months prior to screening or

• Agree to use a condom with spermicide when sexually active with a female partner who is not using an acceptable method of birth control during the study and for 1 month after last study medication administration.

• Agree to refrain from sperm donation during the study and for 1 month after last study medication administration

5. Body weight of 50–100 kg (110-220 pounds), inclusive

6. Body mass index (BMI) ≤ 30

7. Considered to be in stable health in the opinion of the Investigator, as determined by:

• A pre-study physical examination with no clinically significant abnormalities

• A medical history indicating no clinically significant abnormalities;

• Vital signs within normal ranges or if outside of the normal range are not deemed clinically significant in the opinion of the Investigator.

• Liver function tests (ALT/AST, bilirubin and alkaline phosphatase) within normal range

• All other pre-study clinical laboratory findings within normal range, or if outside of the normal range are not deemed clinically significant in the opinion of the Investigator

• 12-lead electrocardiogram (ECG) showing no clinically significant abnormalities.

8. Agree to comply with concomitant medication rules

9. Agree to comply with rules regarding consumption of alcohol, caffeinated beverages (i.e., tea, cola, cocoa, coffee, etc.), and tobacco.

Exclusion Criteria

Subjects who meet any of the following criteria will be excluded from the study.

1. Clinically significant new illness in the 1 month before screening

2. Symptoms or illness compatible with gastrointestinal or respiratory viral syndrome within 4 weeks prior to screening

3. Previous participation in any clinical study with an investigational drug, biologic, or device within 6 weeks prior to the Screening visit

4. History of severe drug or excipient allergy or hypersensitivity

5. Subject who has donated any blood, or had significant blood loss within

56 days of dosing

6. Subject who has donated plasma within 7 days prior to dosing

7. Recent history (within 2 years prior to the screening visit) of alcohol or drug/solvent abuse or a positive screen for alcohol or drugs of abuse, including marijuana, at screening

8. History of or positive Screening tests for hepatitis B, hepatitis C or human immunodeficiency virus (HIV)

9. History of hypertension, coronary artery disease, or any other significant cardiovascular disease

10. History of diabetes

11. Subjects with systolic blood pressure <90 mmHg or diastolic blood pressure <50 mmHg at Screening or Day -1 pre-dose

12. Male subjects with a QTcF >450 msec or female subjects with a QTcF >470 msec on Screening and Day -1 Safety ECG

13. History of unexplained loss of consciousness, epilepsy or other seizure disorder, or cerebrovascular disease

14. Malignancy within 5 years of the screening visit (with the exception of basal cell and squamous cell skin carcinoma)

15. Not suitable to participate in the study in the opinion of the Investigator including an existing physical or mental condition that prevents compliance with the protocol

Number of Subjects

48 subjects Only subjects who discontinue prior to their first dose of IP will be replaced.

Concomitant Medications/ Habitual consumptions

Subjects are prohibited from using any prescribed or non-prescribed systemic or topical medications, including herbal medications, within 7 days of the first dose of IP with the following exceptions: vitamin/mineral supplements or acetaminophen (up to 3 doses per week).

Caffeine intake should not exceed two 6-oz cups of coffee/day or two 12-oz cans of regular caffeinated soda/day from Day -7 through completion of the last study visit (whether scheduled visit of Early Termination Visit).

Use of tobacco or nicotine products is prohibited between Day -28 and completion of the last study visit (whether scheduled visit of Early Termination Visit).

Consumption of alcohol is prohibited between Day -7 and completion of the last study visit (whether scheduled visit or Early Termination Visit).

Outcome Measures:

Safety

Safety will be evaluated by:

• Collection of adverse events

• Physical examination

• Vital signs (blood pressure, heart rate, temperature, respiratory rate)

• Weight

• Laboratory studies:

o CBC with differential and platelets o Serum chemistry o Urinalysis

• ECG

Twelve lead ECG will be performed following recommendations in ICH E14 regarding evaluation of QTc prolongation in patients in early-stage clinical trials. ECGs will be performed in triplicate on Days 1, 2, and 8.

Outcome Measures: PK

BPN-XXXXX concentrations will be determined using a high-pressure liquid chromatography coupled with a mass spectrometer (LC/MS/MS) method. The method will be determined during toxicokinetic studies and then qualification for human application. Qualification will include determination of the limits of quantitation. Bioanalytical methods used in the toxicological studies will be available to the offeror.

Investigational Product

BPN-XXXXX will be provided as API in a bottle for filling 30 and 300 mg capsules.

Instructions for shipping, storage and handling will be provided in the protocol.

The proposed dose levels are 30, 90, 300, 900 and 3000 mg. BPN-XXXXX will be taken in the morning in the fasting state, with 4-8 ounces of water, as needed.

Sample Size Justification

No formal sample size determination was performed. Cohort size is predicated on that typically judged sufficient to characterize safety and PK parameters in first in human clinical trials.

Statistical Analysis

Populations to be Analyzed:

All subjects who receive IP will be included in the safety population. All subjects who receive IP and have at least one post-treatment sample or determination will be included in the PK analysis population. Analysis will be by treatment assignment.

Safety Analysis:

Safety will be evaluated by monitoring AEs, and by change from baseline on examinations and laboratory studies. The AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and preferred term, by severity, by relationship to study drug and study procedure, and by study drug dose. ECG parameters to be analyzed will include heart rate, PR, QRS, QT, QTcB and QTcF intervals. Analysis of other examinations will be specified in the protocol.

PK Analyses

PK parameters will be summarized using descriptive statistics (mean, standard deviation, coefficient of variation [CV], median, minimum, and maximum) by treatment. Geometric means will be determined for AUC0-inf, AUC 0-t, and Cmax.

The following PK parameters will be determined:

• Maximum observed plasma concentration (Cmax) and time of the maximum observed plasma concentration (Tmax), obtained directly from the data without interpolation.

• The apparent terminal elimination rate constant (λZ,), determined by log-linear regression of the terminal plasma concentrations.

• Area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration (AUC0-t), calculated by the linear trapezoidal method.

• Apparent plasma terminal elimination half-life (t1/2), calculated as 0.693/λZ.

Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf) where AUC0-inf = AUC0-t + Ct/λz and Ct is the last measurable concentration.

• Apparent total plasma clearance (CL/F).

• Apparent volume of distribution during the terminal phase (VZ/F).

The full analysis plan will be presented in the protocol.

Performance Study will be performed at 1 center in the United States.

Duration of the study from commencement of Screening to completed data analysis is estimated to be approximately 26 weeks.

Please provide cost estimates for each these additional studies performed as part of this protocol

1) CSF PK collection and analysis

2) MRI Imaging of head

3) CT of head

Table 2: BPN-XXXXX Single Ascending Dose Study Schedule of Assessments and Procedures, Cohorts 1-6

Screenin g Days

Treatment

Days -28 to -2 -1 1 2 3 4 6 8

Informed consent X

Eligibility Criteria X X

Demographics X

Medical, Vision and Ocular History X X

Research Unit In-patient X X X X

Complete Physical Exam X X X X

Vital Signs X X X X X X X

Weight X X X X

Height, BMI X

Urine drug test/ alcohol breath test X X X

Pregnancy Test (females only) X X X

ECG X X X X X X X

Special Screening blood tests (hepatitis B, hepatitis C, HIV) X

Hematology, Chemistry, Urinalysis X X X

Plasma for PK X X X X X

IP Administration in CRU X

Phone contact X

Prior and Concomitant Medications X X X X X X X X

Adverse Events X X X X X X X X

Table 3: Detailed Visit Schedule for Days in Research Unit

-1

2 3

(Cohorts 4-6)

Pre Post Complete Physical Exam X X

Vital Signs X 1 hr 1, 4, 8, 12 hr X X X

Weight X X X

Urine drug test/ alcohol breath test

X

Pregnancy Test (females only)

X ECG (triplicate) X 1 hr 1, 4, 8, 12 hrs 24 hr X X

Hematology, Chemisty, Urinalysis

X

Plasma for PK X X 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 hr

24, 36 hr hr

72 hr

IP Administration in CRU X X X Issue Drug for Home Use X Compliance/ Collect Drug Prior and Concomitant Medications

X X

Adverse Events X X X X X X