Domestic Bedrest SOW v1.3.pdf

BEDREST PLATFORM IMPLEMENTATION SERVICES

Statement of Work (SOW)

1. GENERAL

This SOW is for non-personal services contract to implement the platform services required for the Flywheel Exercise Bedrest Study at the contractor’s facility in support of NASA’s Human Research Program (HRP). The Flywheel Exercise Bedrest Study consists of two parts:

the fundamental bedrest services and the performance of the science measures. This SOW only covers the head-down tilt (HDT) bed rest platform and facility capabilities and services required to implement the Flywheel Exercise study. The study uses strict 6° head-down tilt bed rest as an analog for some of the physiological adaptations experienced by astronauts during spaceflight. ‘Strict’ head-down tilt entails ensuring adherence to the head-down tilt protocol at all times including dining, personal hygiene activities, sleep, and task/test completion. The Flywheel Exercise study will evaluate the adequacy of a NASA-provided flywheel exercise device to address long term exercise requirements for space exploration missions. This custom-built flywheel device uses rotational inertia to provide resistance through a mechanical “yo-yo” action of a spinning mass. While isoinertial flywheel-based exercise has been shown to be effective in promoting positive adaptations in muscle strength and aerobic conditioning, this particular flight-designed device has not been evaluated in a spaceflight-like environment. The purpose of this study is to compare muscle and aerobic outcomes in a group of subjects following a flight-like prescription on the NASA flywheel vs. a control group that does not exercise. The outcomes of the study are crucial to defining potential exercise countermeasure protocol and hardware development for planned space exploration missions.

The Research Operations and Implementation (ROI) element of HRP will provide to the contractor a draft Integrated Requirements Document (IRD) specifying the principal investigator (PI) science requirements for the study. ROI and the contractor will jointly develop the IRD to efficiently integrate the study protocols with the operational processes and capabilities of the contractor’s facility. The contractor may propose additional scientific investigations to be implemented during the study periods. The contractor and HRP will jointly discuss the inclusion of the contractor proposals to ensure they can be accomplished in a manner that enhances, rather than confounds, the HRP-selected studies.

Preliminary definition of inclusion/exclusion criteria and standard diet for this study are included in Attachment 1. Final requirements for inclusion/exclusion criteria and standard diet, as well as any other study specific requirements, shall be documented in the Flywheel Exercise IRD, which will take precedence over Attachment 1.

Optical Coherence Tomography (OCT) measures are critical for validating a bed rest facility.

The OCT device make, model and other considerations need to be identical to OCT measures collected for the International Space Station program and other international bed rest measures. Therefore, the OCT device that meets the required specifications will be furnished by NASA for accommodation at the contractor facility. The OCT arm called “flex arm” will also be included. NASA will provide OCT operations training for the contractor staff that may require travel.

2. OBJECTIVE

The contractor shall provide personnel, equipment, tools, material, and other items necessary to perform all activities necessary to prepare for, conduct, and close out two (2) sequential 60-day bed rest campaigns implementing HRP study requirements as described within this SOW. The contractor shall ensure all work in support of the campaigns tendered to the Government for acceptance conform to the measurable performance standards of quality, timeliness, and quantity specified in this SOW. The contractor shall perform all management functions, including technical and business management, necessary to plan, implement, track, report and deliver the required services described in the SOW.

3. SCOPE OF WORK

The Flywheel Exercise Implementation Services shall consist of two campaigns of strict 60-day head down tilt (HDT) bed rest, each with 12 test subjects. Each campaign must include 14 days of pre-head down tilt baseline data collection and 14 days of post-head down tilt data collection and reconditioning. Each campaign of 12 subjects shall be comprised of six control subjects and six exercise countermeasure subjects for a total N=24 across the two campaigns.

3.1 STUDY IMPLEMENTATION PHASE

3.1.1 The contractor shall work with ROI to define the facility upgrades and integration of study hardware and software requirements. Milestone and implementation schedule will be developed jointly with inputs from all stakeholders.

3.1.2 The contractor shall organize all required training of staff, subjects, and logistics required for implementing the study.

3.1.3 The contractor shall conduct all implementation activities required to complete subject enrollment, baseline data collection (BDC), the head down in-bed phase, and all post bed-rest activities in accordance with the requirements detailed in the IRD, the study protocol and the detailed study schedule for each campaign.

3.1.4 The contractor shall report to ROI any anomalies, off nominal situations, loss of data or loss of subject, adverse events, deviations from the planned testing schedules, or deviations from study requirements as contained in the IRD. Proposed implementation changes that are not in alignment with the approved IRD or IRB shall require ROI approval prior to implementation.

3.1.5 The contractor shall provide activities for the subjects to supplement the study activities. The supplemental activities shall be performed while the subjects maintain strict head down tilt and are intended to alleviate boredom and increase motivation.

3.1.6 Deliverables: Reports regarding anomalous events, IRB reportable incidents, deviations from schedules and protocols within 24 hours of occurrence.

3.2 RECONDITIONING PHASE

3.2.1 The contractor shall conduct reambulation and reconditioning for all test subjects following the bed rest phase as specified in the IRD.

3.2.2 The contractor shall collect data/samples in accordance with the IRD and, as applicable, distribute samples/data from the long-term recovery measurements.

3.3 PLATFORM TRIAL RUN PHASE

3.3.1 The contractor shall demonstrate operation of the bedrest platform capabilities and processes by implementing a minimum 3-day/2-night trial campaign including 6 test subjects. The trial campaign shall implement the campaign planning, staffing, management, and subject care processes planned to be used in the two Flywheel Exercise study campaigns, including implementation of specified tests, measures and countermeasures required for the Flywheel Exercise study.

3.3.2 The contractor shall conduct a Trial Run Readiness Review, with NASA personnel in attendance, confirming the readiness of all equipment, capabilities, and processes at least 1 week prior to the Trial Run.

3.3.3 The contractor shall document all off nominal situations and lessons learned to improve operations during subsequent bedrest campaigns. The contractor shall include feedback provided by ROI to better meet bedrest requirements.

3.3.4 The contractor shall demonstrate successful implementation of each of the equipment, capabilities, subject support, and staffing support listed in sections 1.A. - D. above during the Trial Run. Additionally, the contractor shall implement the following tests and measures in the trial run that are representative of expected PI tests and measures.

1) Bedrest Standard Measures, with the following modifications:

a. OCT during HDT

b. VO2max during HDT

2) Muscle Ultrasound during HDT

3) MRI during HDT

3.4 POST STUDY PHASE

3.4.1 The contractor shall prepare and submit a final report for the Flywheel Exercise study covering both campaigns.

3.4.2 Deliverables: Final study report shall be provided within 60 days of the completion of campaign 2.

4. BEDREST PLATFORM FACILITY AND CAPABILITY REQUIREMENTS

The contractor’s bedrest facility shall provide access to on-site equipment and capabilities to support two Flywheel Exercise 60-day strict head down tilt bedrest campaigns. The contractor shall maintain consistent facility and equipment capabilities across all campaigns to provide a stable and repeatable platform configuration.

4.1 MAJOR EQUIPMENT. The facility shall have the following equipment (at a minimum) available on-site to support the study. All equipment must be capable of maintaining HDT during use.

4.1.1 12 patient beds capable of 6° head down-tilt

4.1.2 Shower capable of 6° head down-tilt

4.1.3 Supine/HDT scale for body weight measurements

4.1.4 Newer generation, wide bore 3T MRI that accommodates use while maintaining HDT

4.1.5 OCT (NASA furnished equipment)

4.1.6 Ultrasound

4.1.7 Metabolic cart for VO2 max measurements

4.1.8 -80 ° C Freezer for biological sample storage

4.1.9 Internal transportation via gurney in the 6° head-down position from bed to test

4.1.10 If transportation outside the facility in the head-down phase of the study is required, subjects will require transport via gurney in the 6° head-down position

4.1.11 Wheelchairs for reambulation phase

4.1.12 Customized pillows that maintain strict HDT

4.1.13 Laptop/Tablet stand that maintain strict HDT

4.1.14 Equipment for screening tests – based on I/E criteria in Attachment 1, A1.

4.1.15 Medical safety equipment

4.2 MAJOR CAPABILITIES. The contractor shall provide the following capabilities (at a minimum) to support the study.

4.2.1 Subject accommodations – The contractor shall provide in-patient rooms (single or double occupancy) for 12 subjects with consistent configuration including temperature control, acoustic mitigation (control of extraneous noise), adjustable lighting capability to support circadian alignment to day and night, and accommodations for subject privacy. Male and female subjects shall have separate accommodations.

4.2.2 Subject monitoring – The contractor shall provide equipment and processes to monitor subjects for subject safety and well-being as well as compliance with strict HDT protocol.

At a minimum this shall include an internal audio communication system and in-room video cameras that are centrally monitored 24/7.

4.2.3 Standardized subject diet – The contractor shall determine individual subject nutritional/caloric intake requirements and provide resources necessary for preparing and serving the standardized diet to test subjects in accordance with the dietary standards provided in Attachment 1 and the IRD. Qualified dietary staff shall develop the menu according to the standardized nutrient intake levels, prepare meals in a metabolic kitchen and provide food items to the test subject in defined amounts. The contractor shall strongly encourage the subjects to consume all food items on their plates. In case of any leftovers on the subjects’ plate, food items shall be separated and weighed to determine the nutrient content of the unfinished food.

4.2.4 Hygiene facilities – The contractor shall provide toileting and shower capabilities for use by the subjects while maintaining HDT.

4.2.5 Large common area to accommodate 4 (minimum) subjects for group activities during

HDT

4.2.6 Standard clinical laboratory capabilities including biosample collection, sample preparation/stabilization, sample storage, and sample processing/testing

4.2.7 IT Capabilities – The contractor shall provide IT infrastructure and data management capabilities to support data collection including externally hosted surveys, storage and distribution to support study requirements. The contractor’s datacenter shall provide alternate power and appropriate redundancy to protect against data loss. The contractor shall provide for data security, allow secure access to data by PIs, and provide fast transfer of large datasets to PIs.

4.2.8 PI hardware accommodation – The contractor shall accommodate hardware that will be provided by the Flywheel Exercise PIs, including storage of hardware and consumables.

The list of PI hardware to be accommodated will be provided in the follow-on Science contract.

4.3 SUBJECT SUPPORT. The contractor shall be responsible for all aspects of subject care from study recruitment through the end of the reconditioning period and release of the subjects.

4.3.1 The contractor shall provide subject recruitment services based on study eligibility criteria, including targeted recruitment efforts for specified candidate groups.

4.3.2 The contractor shall provide subject screening based on study specific inclusion/exclusion criteria. This includes expert assessment of subject suitability to complete the study while maintaining compliance and motivation. The contractor shall select a sufficient number of prime and backup subjects to ensure each of the two campaigns achieve 12 subjects while meeting overall study goals for subject gender mix.

4.3.3 The contractor shall provide remuneration for the subjects in accordance with the contractor’s standard practice and approval by the NASA IRB.

4.3.4 The contractor shall provide clinical care of the subjects while they reside at the contractor facility, including health care monitoring of the subjects independent of the study, plans to address clinical findings during the campaigns, and plans for emergency responses. The contractor shall provide monitoring of subject vitals, including but not limited to pulse, blood pressure, weight, height on transition days (start of baseline data collection, HDT, and reambulation), body temperature, humidity, ambient temperature, and bowel movements.

4.3.5 The contractor shall provide medical monitoring during experimental sessions as required by IRB for subject safety and health while performing high risk activities and interventions.

4.3.6 Food and nutritional support – The contractor shall determine the individual nutritional needs of each subject, plan and prepare menu standardization (rotating menu), monitor food consumption and ensure compliance to prescribed nutritional requirements specified in Attachment 1 and the IRD.

4.3.7 Psychological support – The contractor shall provide psychological support services to the subjects during each campaign including support of subject well-being, morale, and motivation to prevent or mitigate relative social isolation, boredom, compliance issues, or drop-out risks.

4.3.8 Physical therapy support – The contractor shall provide physical therapy and therapeutic massage to prevent or mitigate adverse events such as bedsores, deep vein thrombosis (DVT) and musculoskeletal discomfort throughout the HDT phase. The contractor shall provide physical therapy services during the reambulation/reconditioning phase.

4.3.9 Activity coordination - The contractor shall provide activities for the subjects during pre- , in-HDT, and post- phases of each campaign to mitigate subject boredom and provide meaningful social and occupational engagement outside of study protocol activities.

4.4 STAFF CAPABILITIES

4.4.1 The contractor shall provide staffing to support all aspects of subject care during the two campaigns of the study. Staffing to support implementation of specific PI tests and measures will be covered in the Flywheel Exercise Science contract.

4.4.2 The contractor shall provide a Principal Investigator of record for the bedrest study providing scientific and research ethics oversight for the study, study participants and facility. The Principal Investigator must have a demonstrated level of medical and/or scientific research experience appropriate to providing this scientific and ethics oversight.

5. STUDY MANAGEMENT PLANS

The contractor shall develop and maintain a Study Management Plan that provides detailed descriptions of how the Flywheel Exercise Study will be implemented for the entire study period. The status and changes to the implementation of the study shall be discussed at the regular telecons between the contractor and ROI. The contractor shall develop a Trial Run Management Plan covering the specific scope of the Trial Run. The plans shall include the following at a minimum:

5.1.1 Study management team, organizational structure, and management processes, including process for interacting with ROI based on requirements outlined in this SOW and information from a kick-off TIM with ROI.

5.1.2 Detailed resource plan and study schedule

5.1.3 Facilities – list of major equipment and capabilities that will be utilized for the study, including maintenance approach, access and availability, and known plans for upgrade or modification

5.1.4 Staffing – list staff roles, specific areas of expertise, availability and on-call approach, employee type (full or part time, contract, student, etc.), training, and approach to staff interactions and coordination

5.1.5 Subjects – recruitment, screening, selection, remuneration, approach to clinical care, approach to food and nutrition, approach to psychological support, subject monitoring plan, and subject activities plan

5.1.6 Collection and storage of ancillary data values, for example, subject weight, blood pressure (BP), body temperature, nutritional data, and medical / psychological subject data.

5.1.7 Coordination of study specific training and integration and testing of PI hardware and software

5.1.8 Logistics

5.1.9 Data management

5.1.10 Major study management milestones

5.1.11 Products/Deliverables

5.1.12 Development of regulatory or other required documentation

5.1.13 Dependencies (e.g., ROI-provided draft IRD)

5.1.14 Risks and mitigation strategies to include measures to protect subjects from injury or illness

5.1.15 Media/Comm plan

5.1.16 Reporting to ROI/NASA

5.1.17 Issue identification, communication, resolution and decision processes

5.1.18 Contingency planning

5.1.19 Facility and Operations/Test Readiness Reviews

5.1.20 Deliverables:

• Study Management Plan including study schedule

• Trial Run Management Plan

6. INTEGRATED REQUIREMENTS DOCUMENT (IRD)

ROI will provide a draft Integrated Requirements Documents (IRD) for the Flywheel Exercise study to the contractor. The contractor shall analyze the science proposal and related experiment data sheets and provide inputs to the draft IRD specific to platform capabilities/constraints, contractor support requirements or capabilities, and study implementation factors. The contractor shall concur on the baseline version of the Flywheel Exercise IRD. ROI and the contractor shall jointly develop updates to the IRD as required.

The IRD shall be the authoritative document outlining implementation of all research investigations, standard measures, and data management requirements.

Deliverables:

• Inputs to the ROI-provided draft IRD

• Concurrence with the baseline version of the IRD

7. INTEGRATED STUDY PROTOCOL

The contractor shall prepare an Integrated Study Protocol to define detailed implementation of baseline data collection (BDC) and PI experiments for the Flywheel Exercise study, including a preliminary daily testing schedule that will be finalized prior to the Test Readiness Review. The Integrated Study Protocol shall be based on the requirements, constraints, and descriptions of PI science contained in the jointly developed IRD. The IRD shall be the authoritative document describing implementation of all research investigations, standard measures, and data management.

Deliverables:

• Integrated Study Protocol with Preliminary and Final Daily Testing schedules

8. REVIEW AND OVERSIGHT BOARDS

The contractor shall prepare and submit any required protocols for institutional review board (IRB) approval of the Flywheel Exercise study, including amendments. ROI will obtain NASA IRB approval for the PI protocol. The contractor shall remain compliant with all regulatory board requirements and provide ROI sufficient information as required for NASA IRB reporting.

Deliverables:

• Preparation of submission and approval of Study Complement by contractor’s IRB and other applicable regulatory board(s)

9. PI AND INVESTIGATOR WORKING GROUP (IWG) SUPPORT

The contractor shall participate in one IWG for Flywheel Exercise hosted by the ROI team to coordinate the IRD and detailed study plans with all stakeholders including PIs. The contractor shall host and participate in up to 2 additional IWGs to support development of the final integrated study protocol. The contractor shall develop a PI integration schedule in consultation with ROI and support a testing period for all HRP-funded PIs to test and verify their unique hardware, procedures, timelines and testing schedules, and train in-house personnel who will conduct the testing/measurements during the campaigns. The contractor shall update the study plan, daily schedule, procedures, and other documentation as needed and jointly develop updates to the IRD to reflect changes made during the testing period. The contractor shall assist with logistics and set-up of PI specific hardware shipped or carried to the bedrest facility as required.

Deliverables:

• Participation in ROI-hosted IWG and contractor hosting of 1-2 additional IWGs to support development of the final integrated study protocol.

• Detailed schedule for testing, verification, and training of contractor staff for all HRP-funded PIs. Update study plan, daily schedule, procedures, and other documentation as needed and jointly develop updates to the IRD to reflect changes made during the testing period.

10. TEST SUBJECT SELECTION

The contractor shall recruit volunteer test subjects in strict accordance with the Inclusion/Exclusion criteria described in attachment A1 and in the Integrated Requirements Document. Where these documents differ, the IRD shall take precedence. The contractor shall conduct screening, medical qualification/certification, and any non-standard testing required to ensure acceptability of subjects for inclusion into the study. The contractor shall recruit a sufficient subject pool to allow selection of 12 subjects plus backups for each campaign and an equal number of male and female subjects across the 2 campaigns and test conditions.

Deliverables:

• Schedule for recruiting, screening, and selection milestones, and notification of potential risks that may jeopardize recruitment.

• Notification of any deviations/changes from standard NASA screening tests or measures.

• Summary report describing the selected test subjects and backups with respect to their adherence to the inclusion/exclusion criteria not later than 2 weeks prior to each campaign.

11. TEST READINESS REVIEW

The contractor shall conduct a Test Readiness Review (TRR) meeting at least 3 weeks prior to the start of each campaign to ensure all stakeholders’ requirements have been met, all facility and staff capabilities are ready to support the campaign, and the study team is ready to accept test subjects. The Test Readiness Review, which can be virtual, shall include all HRP-funded PIs or designees, as well as ROI and other HRP stakeholders. The result of each TRR is agreement by the contractor and ROI to proceed with implementation of the campaign upon completion of the identified open work items.

Deliverables:

• The Test Readiness Review meeting shall be held not later than 3 weeks prior to admission of the first subject to each Flywheel Exercise campaign.

• Agreement between the contractor and ROI on a plan to address any open items, decisions, and actions shall be completed no later than 1 week after the meeting.

12. COMMUNICATION AND REPORTING

The contractor shall routinely communicate with ROI to ensure the campaigns are implemented in a safe, effective, and efficient manner. The contractor shall participate in regular telecoms organized by ROI to ensure proper coordination across all phases of the study. Minutes shall be provided by ROI via an email summary of decisions, actions, issues, and outstanding questions.

The contractor shall host regular on-site visits by ROI to assess progress and discuss any deviation from the management plan. Communication between the contractor and ROI via email, phone calls, etc. shall also be used as needed to ensure timely communication and to support decision making.

During the implementation phase of each campaign (beginning with the arrival of the first subjects to the bedrest facility), the contractor shall provide weekly written reports, not later than 3 days following the end of each week. Weekly reports shall provide a status of the campaign and each participating subject, any anomalies, off nominal situations, loss of data or loss of subject, adverse events, deviations from the planned testing schedules, and deviations from study protocols as contained in the Integrated Requirements Document (IRD). This includes reporting subject injury or illness on JSC Form 1627 within 24 hours of an injury or illness.

To the extent possible, deviations from study protocols and/or schedules shall be coordinated in advance with ROI. Some deviations shall require ROI approval prior to implementation of a response to the deviation (e.g., actions that would violate or require changes to study documentation including but not limited to IRB/Ethics Board protocols and the IRD). The occurrence of adverse events or medical issues for subjects that require reporting to the JSC Institutional Review Board (IRB) shall be reported to ROI within 24 hours of occurrence. Initial reporting may be via phone but must be followed with a written report.

Following each campaign, the contractor shall submit an interim report within 60 days summarizing the implementation of that campaign, deviations from planned execution, a clinical summary, and lessons learned. Attachment 2 describes the content of the interim campaign report.

Deliverables:

• Participation in regular telecom with ROI.

• Weekly written status reports during the implementation phase of each campaign.

• Proactive communication of requested deviations, adverse events, and issues requiring ROI decisions.

• Interim report for each campaign shall be provided within 60 days of the completion of each campaign.

13. SUMMARY OF PAYMENT MILESTONES:

SOW

section Description Timing % Value

6 Integrated Requirements Document (IRD)

Upon signing of the Flywheel Exercise

IRD

7 Integrated Study Protocol Upon delivery of the Flywheel Exercise Integrated Study Protocol and Preliminary Testing Schedule

8 IRB Approval Upon approval of the institution IRB protocol for the Flywheel Exercise study

3.3 Trial Run Upon completion of the Platform Trial

Run

11 Test Readiness Review Upon receipt of the minutes from each Flywheel Exercise Test Readiness Review

10 + 10

12 Communication and Reporting

Upon receipt of the interim report for each 30-day study period

10 + 10

3.4 Final Report Upon acceptance of the final report for

the Flywheel Exercise study covering both campaigns

A-1

ATTACHMENT 1: INCLUSION/EXCLUSION CRITERIA, AND STANDARD DIET

A1 INCLUSION/EXCLUSION CRITERIA

Inclusion criteria

Candidate subject inclusion criteria for the study will include the following:

• Physically and mentally healthy test subjects that declare their willingness to participate in the entire study and successfully passed the psychological and medical screening

• Aged between 24 and 55 years

• Body mass index between 19 to 30 kg/m2

• Body height between 153 to 190 cm (+/- 2 cm)

• Signed informed consent

• Demonstrable medical insurance and official certificate of absence of criminal record

• No less than 2 SD below the average normal bone mineral density (measured by dual-energy x-ray absorptiometry) for hip and lumbar spine (i.e., mean peak bone mineral density of Caucasian, sex-matched young adults) denoted by T-score (T-score > -2).

Demonstrable dentist certificate

• Hormonal contraception for female participants is allowed, but details (manufacturer, doses, dates) must be reported

• History of single episode prolonged grief or mild depression with no symptoms in the 12 months prior to study start is allowed

Exclusion criteria Candidate subject exclusion criteria for the study will include the following:

• Any infectious, genetic, autoimmune, endocrinological, hematological, cardiovascular, lung, gastroenterological, kidney, rheumatic, muscle, bone, orthopedic, dermatological, gynecological, urological, ophthalmological, otorhinolaryngological, neurological or psychiatric disease that precludes a safe participation in the study or might significantly impact scientific results of the study according to the study physician

• Any ocular condition that would significantly impact visual function

• Drug, medication or alcohol abuse (regular consumption of more than 30 g alcohol/day)

• Smoker within 6 months prior to study

• Any long-term medication use that might significantly impact scientific results of the study

(ex. bis-phosphonate therapy, anti-hypertensives, gastro-esophageal reflux)

• History of more than one depressive episode and/or history of a severe depressive episode, such as requiring inpatient or intensive outpatient treatment

• Special dietary requests, that cannot be provided by the project team (e.g., vegan, vegetarian or other ineligible diet)

A-2

• Claustrophobia

• Increased intraocular pressure

• Hyperopia > +5.0 Diopters

• Astigmatism > 3 Diopters

• History of laser surgery of the eye, glaucoma and retinal surgery

• Significant chronic gastro-esophageal reflux precluding a safe participation in the study

• Clinically relevant allergy (e.g., requirement to carry a stand-by emergency injection), that precludes a safe participation in the study

• History of prolapsed intervertebral disc

• History of chronic back complaints, that precludes a safe participation in the study

• History of kidney stones

• History of thyroid dysfunction

• Anemia: Hemoglobin under normal values*. (Normal values of Hemoglobin for men: 13.0-

17.5 g/dl; women 12.0-16.0 g/dl)

• Elevated risk of thrombosis**

• Inability to successfully complete a 10-minute upright posture test without clinically relevant orthostatic symptoms

• Current or history of hemorrhagic diathesis or coagulations disorders

• History of spinal cord disease, including radiculopathy, myelopathy, or neuropathy

• History of disorders affecting CSF circulation (i.e., hydrocephalus, idiopathic intracranial hypertension)

• Known chronic tinnitus

• Hearing loss (bi-lateral or one-sided) precluding successful participation in the study

• Female candidate is pregnant or breast-feeding

• Female candidate is in menopause or post-menopause, unless on hormone replacement therapy (but not treated with bisphosphonates or anti-resorptive).

• Female candidate stopped hormonal contraception medication up to 3 months prior to study start

• Metal implants (or objects like metallic slivers in the eyes, or bullets or shrapnel in the body) or other kinds of bone synthesis materials, implanted medical devices, tattoos or permanent make-up incompatible with MRI

• Participation in a (clinical) study within the last 3 months before start of this study that significantly confounds participation in the bed-rest study

• Any other condition which makes the test subject unsuitable for study inclusion in the opinion of the project team

* Normal values from: https://www.lab-quade.de/leistungen/?idLoc=1 ** A thrombosis risk stratification will be conducted according to clinical standards: in the anamnesis, the subject will be extensively questioned for thrombosis risk factors and assessed by means of specific analytical laboratory methods for assessing thrombosis risk using https://www.lab-quade.de/leistungen/?idLoc=1

A-3 thrombophilia screening (factor I, protein C and S activities, factor V Leiden, prothrombin mutants, lupus PTT, factor VIII-activity).

A2 STANDARD DIET

The contractor will provide resources necessary for preparing and serving the standardized diet to test subjects. Qualified dietary staff will prepare meals from a metabolic kitchen according to the standardized nutrient intake levels (Table A-1).

A2.1 Basic Nutrient Intake Level

The standardized nutrient intake levels should be regarded either as an adequate range, if a range is mentioned, or as a minimum intake level. For some of these nutrients (vitamins and elements), the recommended intake should be achieved on an average per week. For all other nutrients the recommended intake should be achieved every day. The diet can be modified if needed to meet investigator requirements. The metabolic kitchen staff will develop the menu and provide food items to the test subject in defined amounts. Subjects will consume all food items on their plate. In case of any leftovers on the subjects’ plate, food items will be separated and weighed to determine the nutrient content of the unfinished food.

Table A-1. Standardized Nutrient Intake Levels

A-4

Nutrient Adequate intake

Energy (total energy expenditure, TEE) Basal metabolic rate (BMR) will be measured via indirect calorimetry to get individual data × 1.3 (during bed rest) or × 1.6 (ambulatory during pre- and post-bed rest)

Total fat (%TEE) 30% to 35 %

Saturated fatty acids (%TEE) ≤ 10

Monounsaturated fatty acids (%TEE) ≥ 10

Polyunsaturated fatty acids (%TEE) ≥ 7

Protein g/kgBW/d >1.2, NTE 1.7

Carbohydrates (%TEE) 45-55

Total Fibre (g/d) ≥ 30

Electrolytes and Water

Sodium (g/d) 1.5-2.3

Potassium (g/d) 2.6 for females; 3.4 for males

Calcium (mg/d) 1000 to 1200

Water (ml/kgBW/d) minimum intake 40-50, Vitamins

Biotin (µg/d) 30

Pantothenic Acid (mg/d) 5

Folate (µg/d) 400

Niacin (mg/d) 20

Riboflavin (mg/d) 1.5

Thiamin (mg/d) 1.5

Vitamin B6 (mg/d) 2

Vitamin B12 (µg/d) 2

A-5

Vitamin K (µg/d) 80

Vitamin D (ug/d RE) 5

Vitamin A (µg/d RE) 1000

Vitamin C (mg/d) 100

Vitamin E (mg/d α-TE) 15

Elements

Copper (µg/d) 1500-3000

Fluoride (mg/d) 1.5 – 4

Iodine (µg/d) 150

Iron (mg/d) Male: 10; Female 18

Magnesium (mg/d) 300

Phosphorus (mg/d) 700-1700

Zinc (mg/d) 12-15

A2.2 Dietary Supplements

During screening, serum 25-hydroxyvitamin D levels will be assessed. If subjects’ levels are below the recommended serum values, they will be supplemented individually according to the following formula (40 x (75 – Vitamin D value screening (nmol/l))* body weight (Kg))/ weeks until the start of the study = „Given dose“ (E/day) (according to Groningen et al 2010).

All subjects will receive 1000 IU of Vitamin D supplementation in addition to Vitamin D contained of the diet in the in-house period. Supplementation will stabilize Vitamin D values for all subjects.

A2.3 Dietary Restrictions Other than the Basic Nutrient Requirement

In addition to matching the nutrient intake levels, other dietary restrictions are necessary.

These are:

• No methylxanthine derivatives are allowed (coffee, decaffeinated coffee, black and green tea, energy drinks, chocolate, cola)

• No alcohol intake

• No flavor enhancers

A-6

• No sweat inducing spices (such as chili, hot curry)

ATTACHMENT 2: INTERIM CAMPAIGN REPORT

The interim campaign report for each campaign shall include the following information at a minimum. The contractor shall include additional information as necessary to describe any special circumstances or unexpected events. Note that all information in the interim report must be de-identified and only reference subject numbers.

1. Overview of Campaign

a. Study name, location, duration, subjects

b. IRB approvals

c. Description of study and countermeasures

d. Hypothesis

e. Goals

f. Participating Principal Investigators

2. Flywheel Exercise Study Implementation

a. Technical

b. Management

c. Performance

d. Test Subject Recruitment

e. Countermeasures and Group Allocation

f. Subject Demographics

g. Facility Environmental Conditions

h. HDT Phase Standard Conditions

i. Implementation of Countermeasures

j. Implementation of Controlled Diet

k. Implementation of International Standard Measures

l. Implementation of PI Experiments

m. Implementation of Physical Therapy and Reconditioning

A-7

3. Deviations to the Study Plan

a. Deviations from the 6° HDT Position

b. Deviation from standardized body weight control

c. Deviation from confinement

4. Clinical Report

a. Medical events and therapy

b. Incidental medical findings

5. Lessons Learned during Campaign