Global

Minimal editorial changes

Correct punctuation, etc

Global

Study changed from Phase 3 to Phase 2

Per Food and Drug Administration (FDA) Psychiatry Division feedback received 01 Sep 2021

Global

One Month Lookback (Past Month) version of CAPS‑5 will now be used for efficacy (rather than 1 week lookback in prior version.)

Preferred model for efficacy assessment

Schedule of Assessments

CAPS‑5 will be administered at Baseline, Week 4 and Week 12 now.

Preferred model for efficacy assessment

Synopsis, Sections 7, 13.1

To randomize 220 participants instead of the original 378

With the change from Phase 3 to Phase 2, the power for sample size estimation was reduced from 90% to 80%

Section 13.3.3

There will be an unblinded interim analysis by an Independent Data Monitoring Committee once 50% of the sample has either completed treatment or early terminated.

To confirm safety and efficacy

Schedule of Assessments

(SoA)

Added collection of prior and concomitant medication information for at post-study follow-up visit

Added CAPS-5 Debriefing Scale to be administered at post-study follow-up visit

Added text to footnote g: Urine drug screen to confirm eligibility if Visit 1 results were positive for excluded medication requiring washout or the following: cannabis, amphetamines, opioids, benzodiazepines..

It was intended for prior and concomitant medications to be evaluated at the post-study follow-up visit, but this was not noted in the SoA.

The addition of the CAPS-5 debriefing scale was discussed above in Overall Rationale for the Amendment.

The addition to footnote ‘g’ in the SoA was for clarification of optional urine drug screen testing at Visit 2, with the naming of drugs that might be washed out for participation and therefore would need verification of successful washout at Visit 2

Section 5

Added text: While some work has been done in segments of the population, less work has been done among police officers in Kenya. However, most of the available data indicate high stress levels, probably higher than their colleagues in the west. This is because they have extra challenges including low pay, poor living and working conditions especially housing, lack of transport and supplies and low personnel numbers. Due to their high levels of exposure to potentially traumatic events, many officers are on treatment and follow-up for PTSD. Treatments for PTSD have had varied outcomes, and currently in Kenya there is no specific medication that is targeted at this condition.

This was added back to the protocol to better describe the rationale for this pharmacotherapy trial for the proposed specific PTSD population under study.

Synopsis, Section 8.1

Deleted inclusion criteria 7-8 and replaced with revised criterion 7.

7.            Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

8.            Separate written, signed informed consent will be required if the participant is to join in the optional pharmacogenomic assessment. A decision not to participate in optional pharmacogenomic testing will not affect the participant’s eligibility for the main study

7.            Capable  of reading and understanding English and able to provide written informed consent to participate. Separate written, signed informed consent will be required if the patient is to participate in the optional pharmacogenomic assessment. A decision not to participate in optional pharmacogenomic testing will not affect the subject's eligibility for the main study.

These changes were for clarification and emphasis on the necessity of participants to read and understand English as an entry criterion previously discussed with the PPB.

Synopsis, Section 8.2

Aligned criterion in synopsis and Section 8.2; added wording to exclusion criterion 20: Current moderate or severe sleep apnea not well‑controlled by positive airway pressure (PAP) or oral (mouthpiece) devices.

10.          Unable to successfully wash out of the following medications during screening…buspirone, trazodone, stimulants (eg, amphetamine mixed salts, methylphenidate, lisdexamphetamine, dextroamphetamine, modafanil, armodafanil), or atomoxetine.

Clarification of exclusion criterion 20 to be internally consistent with the intention as described in synopsis and Section 8.2.

Synopsis, Section 8.2

Added new exclusion criterion:
25.          Currently taking strong P450 3A4 inhibitors or inducers (Appendix 3) and no ability to successfully washout according to protocol requirements or if washout is medically unadvisable.

P450 3A4 strong inducers and strong inhibitors, were moved into a separate exclusion for greater clarity and emphasis.

Section 8.3

Added to Randomization Criteria:

3.            At Visit 2, participant is not severely depressed based on MADRS score ≤26

For safety, the Visit 1 exclusion for severe depression, based on a MADRS score >26, was also added as one of the randomization criteria for Visit 2 (Baseline/Randomization). As a randomization criterion, it is now stated as an inclusion of only those not severely depressed based on MADRS score <26 at Visit 2

Section 9.5.1.2

Added text: Rescreening  is allowed with the permission of the MM; no participant can be rescreened more than once.

Rescreening policy had not been explicated in previous versions of protocol, and therefore it was added in this amendment.

Section 9.5.1.4

2.            Obtain demographics, including alcohol, nicotine/tobacco (smoking and/or chewing), and cannabis use.

4.            Obtain prior and current medication history, including all prior PTSD therapies and other treatments for psychiatric indications. Obtain vaccination history for the 90 days prior to Screening Visit.

Additions to clarify the requirements for demographics and prior/concomitant medications.

Section 9.5.7

1. Draw samples for clinical laboratory tests for
   1. Chemistry and hematology
   2. Conduct urine pregnancy test (for women of childbearing potential). Serum pregnancy test may be done at Investigator’s discretion.
2. Conduct visual examination of oral cavity
3. Have the participant complete the following outcome scales (in order):
   1. PTSD Checklist for DSM-5 (PCL-5)
   2. SDS
   3. PROMIS Sleep Disturbance scale
   4. PGIC
   5. CSFQ‑14
4. Administer Depression/Suicidality Scales
   1. MADRS
   2. C‑SSRS, Since Last Visit version
5. Physician to assess CGI‑S and CGI-I (these assessments need to be completed once all other assessments are available for Investigator to review)

To clarify the requirements for early termination visits.

Section 9.5.8

Added text: Finally, after all other procedures and assessments are completed at the post-study follow-up visit (Visit 7), provide the participant with the CAPS-5 Debriefing Scale to complete before discharging the participant from the study.

The timing of administration of the newly incorporated CAPS-5 Debriefing Scale was added to the order of assessments in Section 9.5.9 at Visit 7.

Section 11.2.10

Added Section 11.2.10:

11.2.10. CAPS-5 Debriefing Scale

At the final visit to the clinic, Visit 7, after all other scheduled study measures are completed, the participant will be asked to complete the CAPS-5 Debriefing Scale about the 20 scored items of the CAPS-5. The purpose of this scale is to identify the CAPS-5 items that are most important and relevant to the patients’ experience of their PTSD and whether there was any change in the symptoms over the treatment period. The scale will assess all 20 scored items of CAPS-5 (B1 B5, C1 C2, D1 D7, and E1 E6) with the following instructions for each item:

Please recall the question that started with [the initial probe question for each item, eg, B1 “In the past month, have you had any unwanted memories of your traumatic event(s) while you were awake, so not counting dreams?”]:

1.            Did you think you had this symptom when you had your first (baseline) interview? (yes or no; if you answered “no”, skip 2-4. below and go on to next CAPS-5 item)

2.            If you did have the symptom, how would you rate it on a 1-4 scale as to its importance to you as part of your overall PTSD? (circle one: 1= minimally important, 2 = moderately important, 3 = very important, 4 = it is my worst PTSD symptom)

3.            By the final treatment visit (Visit 6), this symptom was: (circle one: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = not changed, 5 = minimally worse, 6 = much worse, 7 = very much worse)

4.            Do you think it would be possible for someone to understand your PTSD without knowing how much you experienced this symptom, ie, like if you were never asked about it? (yes or no)

The purpose of this scale is to gauge the relative usefulness of CAPS-5 items for assessing improvement in PTSD severity in a treatment trial across all patients completing this trial, P308.

To describe the newly added CAPS-5 Debriefing Scale for exploring content validity of CAPS-5 items as indicated by sponsor to US FDA.

Section 12.1.8

Added text: Retesting is permitted with MM approval.

Clarified that ECG retesting is only allowed if approved by the study MM.

Section 12.1.9

Added text: Clinical laboratory values may be repeated, with MM approval, prior to randomization in order to confirm exclusionary levels for TSH, ALT and/or AST values.

A urine drug screen for drugs of abuse (including cannabis, amphetamines, opioids, benzodiazepines, cocaine) will be collected at Screening Visit 1 and sent to the local laboratory for analysis.

Clarification that retesting of exclusionary levels of TSH, ALT, and/or AST is only allowed if approved by the study medical monitor.

Also clarified all the analytes tested in the urine drug screen at Visit 1.

Table 7

Added: HbA1c

Deleted: Free T4 only if TSH is outside of normal limits

Added HbA1c as a better measure of glucose levels over time to exclude uncontrolled diabetes.

Free T4 testing is now considered unnecessary given accuracy of highly specific TSH testing, so omitted this reflex testing of free T4 level.

Section 12.1.10.5

Any SAEs considered possibly or probably related to the IP and discovered by the Investigator at any time after the study should be reported. Information about all SAEs will be collected and recorded on the AE Form of the eCRF. The Investigator must report within 24 hours of learning of its occurrence any SAEs via electronic data capture (EDC) system (primary method) or by completing the SAE Form in English (only if EDC system is not available) and emailing it to the safety mailbox: Safety_BZA43880@iqvia.com.All SAEs must be reported to Tonix within 1 business day of the first awareness of the event. The Investigator must complete, sign and date the SAE pages, verify the accuracy of the information recorded on the SAE pages with the corresponding source documents, and send a copy by email to Tonix.

Additional follow-up information, if required or available, will also be recorded in the eCRF within 24 hours of receipt, or, alternatively, sent within a Follow-Up SAE Form to the safety mailbox, if EDC is not available.

Any other documentation supporting SAE information, eg, scanned copies, discharge summaries, laboratory reports, X-rays, etc, will be sent to the safety mailbox, if required should all be faxed to Tonix within 1 business day of receipt, and this should be completed on a follow-up SAE form and placed with the original SAE information and kept with the appropriate section of the eCRF and/or study file.

Updated specifics of SAE reporting.

Table 7

Added: HbA1c

Deleted: Free T4 only if TSH is outside of normal limits

Added HbA1c as a better measure of glucose levels over time to exclude uncontrolled diabetes.

Free T4 testing is now considered unnecessary given accuracy of highly specific TSH testing, so omitted this reflex testing of free T4 level.

Section 13.3.4

Added section: The sponsor, Tonix Pharmaceuticals, will arrange unblinding procedures with the selected contract research organization (CRO) for study monitoring/management and with the vendor that runs all statistical analyses for Tonix. The selected CRO will manage the electronic database for collection of all blinded data. Separately, an alternate data manager at the CRO will manage the interactive response technology (IRT) system for collecting minimal information about study visits (site, subject ID, year of birth, sex, visit date, informed consent date), and for generating randomization codes for active drug versus placebo and investigational product bottle code(s) for dispensing appropriate investigational product.

After database lock has been achieved in the study, the CRO data manager in charge of the database securely will send the database to the unblinding statistician at the statistical vendor. At that time, the sponsor will contact the alternate CRO data manager for the IRT system, signing an unblinding document and requesting the unblinding codes to be securely sent to the unblinding statistician at the statistical vendor. This will occur approximately 4 business days prior to sponsor unblinding. The unblinding statistician at the statistical vendor will merge together the database and the unblinding codes. Then the unblinding statistician will conduct top-line analyses of the disposition data, demographics data, primary outcome measure and the key secondary measures analyses, along with top-line safety data, as prespecified in the statistical analysis plan (SAP).

On the chosen day of sponsor unblinding, (the goal is to unblind at study conclusion unless the Data Safety Monitoring Board advises otherwise) the unblinding statistician will provide the sponsor’s unblinding team with the unblinded top-line data. The remaining statistical analyses will be conducted by the unblinding statistician and team over the next 10-14 days, at which time the sponsor will be provided with all tables, listings, and figures as prespecified in the SAP.

Added unblinding procedures back to the protocol. Unblinding procedures were in original protocol and had been incorporated in response to a specific question about the unblinding procedures by the PPB.

Section 16.3

Added text: The Investigator must explain to each participant that he or she is completely free to refuse to enter the study or to withdraw from it at any time. The recruiter will establish the possibility of the officer remaining within the study regions within the study period.

Added text that explains that, in recruitment, it should be established that the potential participant does not have travel plans or the need, for work reasons, to leave the region of the study site during the study period. This is to ensure enrolled participants can comply with the full study procedures, including the in-clinic visits.

Section 19

Added references:
21.          Buuri PW: Levels and perceptions of stress among Administration Police Officers, a case of Nairobi County. University of Nairobi, Kenya, 2011.

22.          Coventry PA, Meader N, Melton H, Temple M, Dale H, Wright K, Cloitre M, Karatzias T, Bisson J, Roberts NP, et al: Psychological and pharmacological interventions for posttraumatic stress disorder and comorbid mental health problems following complex traumatic events: Systematic review and component network meta-analysis. PLOS Medicine 2020, 17:e1003262.

23.          Nisenoff CD: Psychotherapeutic and adjunctive pharmacologic approaches to treating posttraumatic stress disorder. Psychiatry (Edgmont) 2008, 5:42-51.

24.          APA: American Psychological Association; Guideline Development Panel for the Treatment of PTSD in Adults: Summary of the clinical practice guideline for the treatment of posttraumatic stress disorder (PTSD) in adults. American Psychologist 2019, 74:596-607.

25.          Institute of M: Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press; 2008.

26.          Stein DJ, Ipser JC, Seedat S: Pharmacotherapy for post traumatic stress disorder (PTSD). The Cochrane database of systematic reviews 2006, 2006:Cd00279

27.          Ravindran LN, Stein MB: Pharmacotherapy of PTSD: premises, principles, and priorities. Brain research 2009, 1293:24-39.

28.          Harpaz-Rotem I, Rosenheck RA, Mohamed S, Desai RA: Pharmacologic treatment of posttraumatic stress disorder among privately insured Americans. Psychiatric services (Washington, DC) 2008, 59:1184-1190.

29.          Mohamed S, Rosenheck RA: Pharmacotherapy of PTSD in the U.S. Department of Veterans Affairs: diagnostic- and symptom-guided drug selection. The Journal of clinical psychiatry 2008, 69:959-965.

To support citations in the sections of text added back in this amendment, the references have been added back as well.

Appendix 2

Added appendix with prior Protocol Amendment History

For clarification of the protocol amendments.

Appendix 3

Added appendix containing list of CYP3A4 inhibitors and inducers which shows which specifically are considered strong inhibitors or inducers and therefore are exclusionary.

Clarifying information for new exclusion criterion 25