NCT03679975 A Single Center Study to Evaluate the Effect of Riluzole Oral Soluble Film on Swallowing Safety in Individuals With Amyotrophic Lateral Sclerosis Protocol 18-Oct-2017 Protocol Number: 17MO1R-0012 Swallowing Safety in ALS Version No 2.0, October 18, 2017 Riluzole Oral Soluble Film A Single Center Study to Evaluate the Effect of Riluzole Oral Soluble Film on Swallowing Safety in Individuals With Amyotrophic Lateral Sclerosis Amendment 1 Summary of Changes from Version 1.0 (July 27, 2017) to Version 2.0 (October 18, 2017) Note: Major changes described in the following table have been made in this document to address the following issues: • Additional exclusion added to clarify the exclusion for the PAS score applies to any previous swallowing studies • Additional exclusion added for subjects with a history of two or more episodes of aspiration pneumonia requiring hospitalization • Modified hepatic function exclusion requirement for subjects currently on Riluzole • Modified hepatic function exclusion requirement for subjects receiving Riluzole for the first time • Added description of comprehensive and brief physical examinations and comprehensive neurological and brief neurological examinations Few minor changes involving wordsmithing for clarity and consistency, punctuation, and correction of typos have also been made but are not included in this table because they are not substantive changes. However, they are visible in the tracked-changes version of the protocol CONFIDENTIAL INFORMATION The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly prohibited without written consent from MonoSol Rx LLC. Page 1 of 55 Protocol Number: 17MO1R-0012 Swallowing Safety in ALS Version No 2.0, October 18, 2017 Riluzole Oral Soluble Film Version No 1.0 July Amendment 1 (Version 2.0) Section 27, 2017 October 18, 2017 Rationale 3. Synopsis p 7 Additional exclusions added – 2. Subjects with a prior in response to Information Exclusion swallowing study that has Request (IR) - IND Criteria shown a PAS of 3 or greater 130939-Comments on new protocol 3. Subjects with a history of submission/SN0003_24_Au two or more episodes of gust_2017 aspiration pneumonia requiring hospitalization 3. p 7 p 7 Changed to be consistent Synopsis – 8. Subjects with 10. Subjects currently with the Reference Listed Exclusion Drug (RLD), RILUTEK hepatic impairment taking riluzole with ALT Criteria (NDA 020599) label as defined by levels greater than 5 times baseline elevations upper limit of normal or with of serum evidence of clinical jaundice. aminotransferases (Riluzole should be greater than 5 discontinued in these times upper limit of patients). normal or evidence of liver dysfunction (e.g., elevated bilirubin ). 3. Synopsis P 7 Added to be consistent with – 11. Subjects who will be the Reference Listed Drug Exclusion receiving riluzole for the first (RLD), RILUTEK (NDA Criteria time who exhibit baseline 020599) label elevations of several LFTs (especially elevated bilirubin). (These findings at baseline should preclude the use of riluzole including ROSF.). 8.1.2 p 18 Additional exclusions added Exclusion 2. Subjects with a prior in response to Information Request (IR) - IND CONFIDENTIAL INFORMATION The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly prohibited without written consent from MonoSol Rx LLC. Page 2 of 55 Protocol Number: 17MO1R-0012 Swallowing Safety in ALS Version No 2.0, October 18, 2017 Riluzole Oral Soluble Film Version No 1.0 July Amendment 1 (Version 2.0) Section 27, 2017 October 18, 2017 Rationale Criteria swallowing study that has 130939-Comments on new shown a PAS of 3 or greater protocol submission/SN0003_24_Au 3. Subjects with a history of gust_2017 two or more episodes of aspiration pneumonia requiring hospitalization 8.1.2 P 19 P 19 Changed to be consistent Exclusion with the Reference Listed 8. Subjects with 10.. Subjects currently Criteria Drug (RLD), RILUTEK hepatic impairment taking riluzole with ALT (NDA 020599) label as defined by levels greater than 5 times baseline elevations of upper limit of normal or with serum evidence of clinical jaundice. aminotransferases (Riluzole should be greater than 5 times discontinued in these patients upper limit of normal .) or evidence of liver dysfunction (e.g., elevated bilirubin ). 8.1.2 P 19 Added to be consistent with Exclusion 11. Subjects who will be the Reference Listed Drug Criteria receiving riluzole for the first (RLD), RILUTEK (NDA time who exhibit baseline 020599) label elevations of several LFTs (especially elevated bilirubin). (These findings at baseline should preclude the use of riluzole including ROSF.). 10.2.2.1. P 27 Added in response to Videofluor The start time and finish time Information Request (IR) - oscopy for the standardized bolus IND 130939-Comments on Swallow protocol will be recorded for new protocol Study both VFSS 1 and VFSS 2. submission/SN0003_24_Au (VFSS 1- gust_2017 PAS) CONFIDENTIAL INFORMATION The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly prohibited without written consent from MonoSol Rx LLC. Page 3 of 55 Protocol Number: 17MO1R-0012 Swallowing Safety in ALS Version No 2.0, October 18, 2017 Riluzole Oral Soluble Film Version No 1.0 July Amendment 1 (Version 2.0) Section 27, 2017 October 18, 2017 Rationale 10.2.2.1. P 26 P 28 Added in response to Videofluor Immediately …sulcus, , and the time of Information Request (IR) - oscopy following VFSS 1- administration will be IND 130939-Comments on Swallow PAS, the patient will recorded. new protocol Study then be administered submission/SN0003_24_Au (VFSS 1- ROSF on the dorsum gust_2017 PAS) of tongue along the median lingual sulcus. 10.2.2.1. P 28 Added in response to Videofluor The investigator should Information Request (IR) - oscopy record whether or not ROSF IND 130939-Comments on Swallow is fully dissolved at 3 minutes new protocol Study after dosing. In the event that submission/SN0003_24_Au gust_2017 (VFSS 1- ROSF is not fully dissolved at PAS) 3 minutes, the investigator will record the time that it is confirmed that ROSF is fully dissolved. 10.3.6. P 30 The CRO managing the Clin Subjects will undergo a protocol requested a ical comprehensive physical and description of the Assessment neurological examination at comprehensive and the s screening, and a brief physical brief physical exam and the and neurological examination neurological exam and brief at Visit 1 following the neurological exam second VFSS. The comprehensive physical examination will include complete vital signs, weight, height, general appearance, and evaluation of systems: head, ears, eyes, nose, and throat; respiratory; abdomen; lymph nodes; spine; skin; cardiovascular; and CONFIDENTIAL INFORMATION The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly prohibited without written consent from MonoSol Rx LLC. Page 4 of 55 Protocol Number: 17MO1R-0012 Swallowing Safety in ALS Version No 2.0, October 18, 2017 Riluzole Oral Soluble Film Version No 1.0 July Amendment 1 (Version 2.0) Section 27, 2017 October 18, 2017 Rationale extremities. The brief general physical examination will include abbreviated vital signs (blood pressure, heart rate, respiratory rate), and examination of the cardiovascular and respiratory systems and abdomen. Other elements may be included depending on symptoms or physical findings. The comprehensive neurological examination will include (as permitted by the patient’s capabilities) cranial nerves 2-12, muscle tone and strength, tendon reflexes and plantar response, sensory function (pain, light touch, position, vibration), coordination (finger-nose), and gait. The brief neurological examination will include cranial nerves 2-12, muscle strength, tendon reflexes, plantar response, and sensory function (pain, light touch, position, vibration). Other elements may be included depending on symptoms or physical findings 10.3.12. P 34 The CRO managing the Phy Subjects will undergo a protocol requested a sical and comprehensive physical and description of the Neurologic neurological examination at comprehensive and the al screening, and a brief physical brief physical exam and the Examinatio neurological exam and brief CONFIDENTIAL INFORMATION The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly prohibited without written consent from MonoSol Rx LLC. Page 5 of 55 Protocol Number: 17MO1R-0012 Swallowing Safety in ALS Version No 2.0, October 18, 2017 Riluzole Oral Soluble Film Version No 1.0 July Amendment 1 (Version 2.0) Section 27, 2017 October 18, 2017 Rationale n and neurological examination neurological exam at Visit 1 following the second VFSS. The comprehensive physical examination will include complete vital signs, weight, height, general appearance, and evaluation of systems: head, ears, eyes, nose, and throat; respiratory; abdomen; lymph nodes; spine; skin; cardiovascular; and extremities. The brief general physical examination will include abbreviated vital signs (blood pressure, heart rate, respiratory rate), and examination of the cardiovascular and respiratory systems and abdomen. Other elements may be included depending on symptoms or physical findings.