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Include a copy of the Objectives/Endpoints Table including primary and secondary endpoints only from Section 3 of the protocol and follow all the same instructions. Not all trials will have a complete estimand. Do not include exploratory endpoints in the synopsis.

see Template instructions

Enter the numeric value for the number of arms in the trial. For trials with a different number of arms in different periods, populate this field based on the total number of arms.

For designs in which these details may differ in one or more trial periods, answer according to the portion of the trial in which the highest number of blinded roles occurs. More details can be provided in Section 6.6 of the protocol. Blinded roles: The following roles indicated will not be made aware of the treatment group assignment during the trial: [blinded roles] Not applicable (No blinding) indicates an open-label trial.

State the expected number of participants to be assigned to trial intervention/enrolled. Indicate whether the number provided is the target or maximum number of individuals to be randomly assigned to trial intervention/enrolled. A [Target/ Maximum] of [[Enter Number of Participants]] participants will be [randomly assigned to trial intervention/ enrolled].

See Template instructions.

Indicate whether any committee(s) will be reviewing data while the trial is ongoing, and the type of committee. Common examples include Data Monitoring Committee, Dose Escalation Committee, or Endpoint Adjudication Committee; describe others, if applicable. List independent committees in the space indicated. Other committees may be included at the Sponsor’s discretion in the separate space provided. Committees listed here should be fully described in Section 11.3. Indicate N/A if no independent committees will be involved in the trial. Delete Other Committees if not applicable.

The purpose of this section is to provide a visual depiction of the trial design, orienting users of the protocol to the key features of the design. The schema depicts the trial arms, the flow of individual participants through the progression of trial period(s)/epochs (such as screening, washout/run-in, intervention, and key milestones [for example, randomisation, cross-over, end of treatment]). For complex trials, additional schemas may be added to describe activities or trial periods in greater detail.

The schedule of activities must capture the procedures that will be accomplished at each trial visit, and all contact with participants, for example, telephone contacts. This includes any tests that are used for eligibility, participant randomisation or stratification, or decisions on trial intervention discontinuation. Allowable windows should be stated for all visits and procedures. A tabular format is recommended.

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Explain why the trial is needed, why the research questions being asked are important. Do not restate the IB.

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The benefit summary should be written from the perspective of an individual participant, and should describe any physical, psychological, social, legal, or any other potential benefits to individual participants as a result of participating in the trial, addressing immediate potential benefits and/or long-range potential benefits. Clearly state if no benefits to an individual participant can be anticipated, or if potential benefits are unknown. For early clinical trials such as Phase 1, benefits for an individual participant (other than those of altruism) are expected to be minimal. Benefits to society in general may also be included but should be described separately.

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Trial Intervention - Describe risks related to trial-specific treatments and interventions. For the protocol, focus only on the relevant key risks for THIS trial. Provide a brief description of strategies to mitigate identified risks or provide a cross-reference to the relevant protocol section.

Trial Procedures - Consider risks associated with the design (for example, placebo arm) and procedures specific to THIS trial (for example, biopsies), and any measures to control the risks. Provide a brief description of strategies to mitigate identified risks or provide a cross-reference to the relevant protocol section. This is not intended to be an exhaustive list of all possible risks associated with trial procedures but should focus on the unique risks inherent in the design or less common or high-risk procedures. As above, provide a brief description of strategies to mitigate identified risks or provide a cross-reference to the relevant protocol section.

Other - Consider risks associated with other items (for example, comparators, challenge agents, imaging agents, medical devices). Insert a line for each, as needed.

Provide a succinct, concluding statement on the perceived balance between risks that have been identified from cumulative safety data, protocol procedures, and anticipated efficacy/benefits within the context of the proposed trial. Risks need to be assessed against the benefits for the individual participant at least once a year.

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Enter 'Primary' or 'Secondary' or 'Exploratory' as the data value.

Precisely define each clinical question of interest by stating each trial objective.

Enter the description of the Endpoint (measured variable).

Describe the attributes that construct the estimand: the treatment condition of interest, the population of participants targeted by the clinical question of interest, other intercurrent events (if applicable), a population level summary, and the endpoint (or variable) specified in the table above.

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see Template instructions

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If applicable, describe any stakeholder (for example, patient, healthcare professional and patient advocacy groups) involvement in the design of the trial and any suggestions implemented.

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Provide a rationale for the trial intervention model selected in Section 4.1, Description of Trial Design with a cross-reference to Section 6.2, Rationale for Investigational Intervention(s). Rationale for choice of comparator, if applicable, should be described separately in Section 4.2.5, Rationale for Comparator. A rationale for the choice of trial population should be described separately in Section 5.1, Description of Trial Population and Rationale.

Provide a rationale that the trial duration is appropriate for a reliable and relevant evaluation of the trial intervention per the trial objective(s).

Provide a rationale that the trial endpoint(s) described in Section 3, Trial Objectives, Endpoints, and Estimands, are clinically relevant and provide a reliable and valid measurement of the intended intervention effect.

If applicable, provide a rationale for any interim analysis planned with respect to its purpose (for example, stopping the trial early for efficacy or futility) and timing.

If applicable, provide a rationale for the type of control selected for the trial (for example, placebo, active drug, combination, historical). Describe any known or potential problems associated with the control group selected in light of the specific disease and intervention(s) being studied. If comparators will differ by region, describe.

If applicable, provide a rationale for the use of an adaptive or novel design.

Discuss rationale for any additional aspects of the design not addressed above.

If applicable, describe any trial-specific stopping rules, including guidance on when the trial should be stopped for safety reasons, when a cohort or dose escalation should be terminated, and/or when a given treatment arm should be terminated.

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If applicable, describe when any of the stopping rules may result in a temporary halt of enrollment into the trial and criteria for restarting enrollment.

Define key timepoints in the trial, including trial start and end dates. For example, a key timepoint definition for start of trial might be when the informed consent is signed by the first participant and a key timepoint definition for end of trial might be when participants are no longer being examined or the last participant’s last study assessment has occurred. If applicable, consider local regulatory requirements for these and other definitions (for example, the first act of recruitment). If appropriate, provide a cross-reference to Section 11.6

If applicable, describe any possibilities for access to trial intervention, if any, beyond completion of the trial. Planned extension trials, if described above in Section 4.1 do not need to be repeated.

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Describe the population selected (for example, healthy participants, adult participants, paediatric participants) and how the enrollment criteria reflect the populations that are likely to use the drug if approved. Specify the population age range (for example, ≤3 months, ≥18 to ≤80 years old) including the time point at which qualification for age criteria is determined (for example, at time of screening vs randomization for paediatric trials). Specify any key diagnostic criteria for the population (for example, “acute lung injury”, or a specific biomarker profile). If applicable, describe similar conditions or diseases and their differential diagnosis. Provide a rationale for the trial population ensuring that the population selected is well defined and clinically recognisable. Describe how the selected population can meet the trial objectives and how the enrollment criteria reflects the targeted populations. Justify whether the trial intervention is to be evaluated in paediatric participants, in adults unable to consent for themselves, other vulnerable participant populations, or those that may respond to the trial intervention differently (for example, elderly, hepatic or renally impaired, or immunocompromised participants).

Inclusion criteria are characteristics that define the trial population, for example, those criteria that every potential participant must satisfy, to qualify for trial entry.

Exclusion criteria are characteristics that make an individual ineligible for participation.

In the following subsections, describe any restrictions during the trial pertaining to lifestyle and/or diet, intake of caffeine, alcohol, or tobacco, or physical and other activities. If not applicable, include a statement that no restrictions are required.

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If applicable, describe any restrictions on diet (for example, food and drink restrictions, timing of meals relative to dosing).

If applicable, describe any restrictions on the intake of caffeine, alcohol, tobacco, or other restrictions.

If applicable, describe any restrictions on activity (for example, in first-in-human trials, activity may be restricted by ensuring participants remain in bed for 4 to 6 hours after dosing).

If applicable, describe restrictions on any other activity (for example, blood or tissue donation); or any other activity restrictions, such as on driving, heavy machinery use, or sun exposure.

Indicate how screen failure will be handled in the trial, including conditions and criteria upon which rescreening is acceptable. If applicable, indicate the circumstances and time window under which a repeat procedure is allowed for screen failure relating to specific inclusion/exclusion criteria for the trial.

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The investigational trial intervention(s) should be described concisely in a table. Describe the investigational trial intervention to be administered in each arm of the trial and for each period of the trial including route and mode of administration, dose, dosage regimen, duration of intervention, use, packaging and labelling. Refer to approved regional labelling, as appropriate. For drug/device combination products, include details on the configuration and use of the device and device manufacturer. A device user manual may be referenced in this section.

Provide a rationale for the selection of the dose(s) or dose range, the route of administration, and dosing regimen of the investigational trial intervention. This rationale should include relevant results from previous preclinical studies and clinical trials that support selection of the dose and regimen. Discuss impact of differences in study population characteristics (for example, age, sex and/or race) which could lead to differences in pharmacokinetics and pharmacodynamics in this study as compared to previous studies. If applicable, justify any differences in dose regimen or therapeutic use relative to approved labelling. Describe prior trials and other information that support the dose and/or dose regimen of the investigational intervention. Include a rationale for prospective dose adjustments incorporated in the trial, if any.

Describe the detailed procedures for administration of each participant's dose of investigational trial intervention. This may include the timing of dosing (for example, time of day, interval), the duration (for example, the length of time participants will be administered the investigational trial intervention), the planned route of administration (for example, oral, nasal, intramuscular), and the timing of dosing relative to meals. Include any specific instructions to trial participants about when or how to prepare and take the dose(s) and how delayed or missed doses should be handled. Dose escalation or cohort expansion as part of the overall design should be covered in Section 4.1 (Description of Trial Design).

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For each participant, describe any dose modifications allowed, including conditions for such dose modifications, particularly regarding failure to respond or safety concerns. State any minimum period required before a participant’s dose might be raised to the next higher dose or dose range. Include whether it is permissible to start and stop treatment and how dose reductions (if permitted) are to be managed. Information on stopping investigational trial intervention for an individua participant due to safety/other reasons should be detailed in Section 7, Participant Discontinuation of Trial Intervention and Withdrawal from Trial.

Describe what is meant by investigational trial intervention overdose. Provide any available information on managing the overdose and ensure it is consistent with the Investigator’s Brochure or product labelling, cross-references these documents as applicable.

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Describe any preparation of the investigational trial intervention, and when necessary, by whom. When applicable, describe the maximum hold time once thawed/mixed before administration. Include thawing, diluting, mixing, and reconstitution/preparation instructions in this section. For drug/device combination products, include any relevant assembly or use instructions and reference the package insert that is provided separately. If the instructions are lengthy or complicated, it is acceptable to reference the package insert (if applicable) or include instructions in a separate document(s) provided to the site (for example, a pharmacy manual). If the latter, reference the separate documents.

Describe storage and handling requirements (for example, protection from light, temperature, humidity) for the investigational trial intervention(s). For trials in which multi-dose vials are utilised, provide additional information regarding stability and expiration time after initial use (for example, the seal is broken). State how the investigational trial intervention(s) will be provided to the Investigator. If applicable, describe the kits, packaging, or other material of the investigational trial intervention for blinding purposes. If the instructions are lengthy or complicated, it is acceptable to reference the package insert (if applicable) or include instructions in a separate document(s) provided to the site (for example, a pharmacy manual). If the latter, reference the separate documents.

Describe the accountability method, including how the investigational trial intervention will be distributed and related details, including: • how and by whom the investigational trial intervention will be distributed • participation of a drug storage repository or pharmacy, if applicable, • plans for disposal or return of unused product, • if applicable, plans for reconciliation of investigational trial intervention.

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Describe the method of assigning participants to investigational trial intervention without being so specific that blinding or randomisation might be compromised. If assignment to investigational trial intervention is by randomisation, describe when randomisation occurs relative to screening. State that at enrollment, participant identification codes should be assigned. If adaptive randomisation or other methods of covariate balancing/minimisation are employed, include a cross-reference to the methods of analysis in Section 10, Statistical Considerations. As applicable, details regarding the implementation of procedures to minimise bias should be described.

Describe the randomisation procedures (for example, central randomisation procedures), the method used to generate the randomisation schedule (for example, computer generated), the source of the randomisation schedule (for example, sponsor, investigator, or other), and whether or not IxRS will be used. To maintain the integrity of the blinding, do not include the block size. Describe the use and validation of any computer systems and programmes used for randomisation.

Describe efforts to ensure that the investigational trial intervention(s) are as indistinguishable as possible. Plans for the maintenance of randomisation codes and appropriate blinding for the trial should be described. Procedures for planned and unplanned (for example, safety events) breaking of randomisation codes should be provided. If the trial allows for some investigators or other designated staff to remain unblinded (for example, to allow them to adjust investigational trial intervention), the means of maintaining the blinding for other investigators or staff should be explained. Measures to prevent unblinding by laboratory measurements or while performing study assessments, if used, should be described.

Describe the criteria for breaking the trial blind or participant code. Describe the circumstances in which the blinding would be broken for an individual or for all participants and who has responsibility. Include the procedure for emergency unblinding such as via IxRS or code envelopes as well as documentation of unblinding. Indicate to whom the intentional and unintentional unblinding should be reported.

Describe measures employed to ensure and document dosing information and investigational trial intervention compliance (for example, accountability records, diary cards, or concentration measurements). Include a description of what documents are mandatory to complete (for example, participant drug log) and what source data/records will be used to document investigational trial intervention compliance.

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Non-investigational interventions are products used in the context of the trial but are not part of trial objectives and are not investigational trial intervention. Describe background interventions, including administration and any conditions for use.

List all rescue medications, treatments, and/or procedures, including any relevant instructions about their administration and any conditions for their use. If administration of rescue therapy leads to the temporary discontinuation of trial intervention or a participant’s withdrawal from the trial, refer to Section 7, Participant Discontinuation of Trial Intervention and Withdrawal from Trial.

If applicable, describe the use of other non-investigational or auxiliary therapy, for example, challenge agents or diagnostics.

Describe the concomitant medications, supplements, complementary and alternative therapies, treatments, and/or procedures which are allowed or prohibited during the trial, and include details about when the information will be collected (for example, screening, all visits). This section should be consistent with the medication restrictions in the inclusion/exclusion criteria previously listed.

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If applicable, describe any prohibited concomitant therapy.

If applicable, describe any permitted concomitant therapy.

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Discontinuation of trial intervention for a participant occurs when trial intervention is stopped earlier than the protocol planned duration. Describe the criteria for discontinuation of a participant from any trial intervention, carefully evaluating which are appropriate for the trial population and therapy being studied. Specify whether participants who discontinue trial intervention can or cannot continue the trial (continue trial visits). Refer to the Section 1.3 Schedule of Activities for assessments to be performed at the time of and following discontinuation of trial intervention. Explain the process for collecting and recording the detailed reasons for discontinuing trial intervention(s).

Describe • the criteria for temporary discontinuation or interruption of trial intervention for an individual participant • what to do and which restrictions still apply if the participant needs to temporarily discontinue or interrupt trial intervention • whether they will continue in the trial, and • whether all, or specify which, assessments will be performed for the stated duration of the trial. Details of any rechallenge or restart after a safety-related event should be included in Section 7.1.3, Rechallenge.

Describe the criteria for rechallenge/restarting trial intervention, how to perform rechallenge, number of rechallenges allowed during the trial, and whether all, or specify which, assessments will be performed for the stated duration of the trial. If rechallenge is not allowed, state this.

Describe the criteria for participant withdrawal from the trial. Describe the reason for withdrawal and the type and data to be collected for the final assessments with reference to the schedule of activities for the participant end of study visit unless provided in another section.

Describe the measures to be taken to reduce the frequency of participants lost to follow up. Describe how the trial will define and address participants who are lost to follow-up to help limit the amount and impact of missing data. Describe the nature and duration of follow-up, as appropriate.

If applicable, describe any trial-specific stopping rules that would apply to individual participants such as treatment or study non-compliance or due to safety reasons. Address the procedure ensuring alignment with the intercurrent events and their handling strategies introduced in Section 3.

• Describe the assessments and procedures required during each phase of the trial. Provide details that are not already presented in the SoA, taking care not to duplicate information. • Describe methods, training, tools, instruments/questionnaires, calibration methods, etc. that will be used to record and assess data and ensure consistency across centres and participants. Include instructions on timing/conditions of assessments and if a specifically qualified person should be performing these assessments. Describe whether centralised readings and measurements will be utilised. • Reference the literature for the validation of scales/instruments/questionnaires/assays. • Instructions or protocols for specialised tests and scales/instruments/questionnaires/assays may be presented in an appendix or a separate document and cross-referenced. • If the trial includes qualitative interviews, describe these evaluations. • If COA measures are utilised, include instructions for the investigators per local guidance. All descriptions related to COA parameters should be fully integrated into the appropriate sections of the protocol; separate COA sections should not be created in the protocol. • Include minimums and limits for procedures (for example, number of imaging procedures/biopsies, radiation exposure, etc.) if appropriate to the trial.

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Describe any assessments and procedures that are unique to screening/baseline (for example, collection of data on participant characteristics, assessments/procedures performed for the purpose of determining eligibility or for stratification) in this section. Describe screening and baseline assessments and procedures separately if screening and baseline are performed at different visits.

Describe efficacy assessments and procedures in this section. Cross-refer to Section 8.7 if immunogenicity assessments are used in efficacy determination.

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Include any specific instructions for the collection and interpretation of physical examinations.

Include any specific instructions for the collection and interpretation of vital signs.

Include any specific instructions for the collection, interpretation, and archiving of ECGs.

Include any specific instructions for the collection and interpretation of clinical laboratory assessments. • Type of laboratory (central/local/hybrid) • acceptability of additional tests deemed necessary by the investigator or local regulations • instructions for situations in which central laboratory results are not available in time for trial intervention and/or response evaluation, or in the event of a severe disruption (for example, a pandemic or natural disaster) • treatment algorithms for results out of normal range • Cross-refer to Section 13.2 for lab assessment panels

Optional section to specify pregnancy testing requirements.

If the trial meets any of the criteria requiring suicidal ideation and behaviour risk monitoring by the guidance/guideline in each region, include justification for the need for suicidal ideation and behaviour risk monitoring in the study and add any specific instructions for the collection and interpretation of the assessment. In case this is an AESI in the study, justification will also need to be provided in the appropriate subsection of Section 9.4.

Include any specific instructions for the collection and assay of samples and interpretation of PK assessments. If pharmacokinetic testing is not included in the study, state Not Applicable. • Describe the biological sample(s) collected, the handling of samples, and the assay method. o Specific sample collection and processing instructions can be described in an appendix or a separate document and cross-referenced. • Describe the retention time for the samples (ensuring alignment with the ICF). • Indicate the types of analyses that may be studied for each sample.

Include any specific instructions for the collection and assay of samples for genetic analysis. If genetic testing is not included in the study, state Not Applicable. • Describe the biological samples that will be collected (for example, tissue, serum, plasma, etc.), handling of samples, and the assay method. o Specific sample collection and processing instructions can be described in an appendix or a separate document and cross-referenced. • Describe the retention time for the samples (ensuring alignment with the ICF). • Indicate the types of analyses that may be studied for each sample.

Include any specific instructions for the collection of samples and assessment of biomarkers, including pharmacodynamics. If biomarker or pharmacodynamic testing is not included in the study, state Not Applicable. • Describe the biological samples that will be collected (for example, tissue, serum, plasma, etc.). o Specific sample collection and processing instructions can be described in an appendix or a separate document and cross-referenced. • Describe the retention time for the samples (ensuring alignment with the ICF). • Indicate the types of biomarkers that will be studied for each sample. • Specify whether each sample is optional or required. Required samples must be based on a protocol objective.