Clinical trial NCT04157686
Conditions: Glabellar Lines Lateral Canthal Lines
Sponsor: Medy-Tox
Start date: 2019-10-23; Completion date: 2023-02-16
Enrollment: 957 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the long-term safety of MT10109L in the treatment of GL and/or LCL in participants with moderate to severe GL and/or LCL.

Detailed description:
Study MT10109L-004 is an open-label extension involving participants from studies MT10109L-001 (NCT03795922), -002 (NCT03785145), -005 (NCT03721016), and -006 (NCT03732833) (referred to as Lead-In studies). The objective is to evaluate long term safety of MT10109L. Participants will include those who completed the global lead-in studies and meet the eligibility criteria for entering this open-label extension study.

Participants who meet retreatment criteria will receive MT10109L administered in the same treatment area(s) with the same number of injections and injection sites as in their lead-in studies.

The safety and efficacy data from the lead-in and this open-label extension will be summarized.

Arms: arm 1: The participant pool in this arm are from the MT10109L-001 lead-in study (NCT03795922), who received Placebo in period 1 and MT10109L Dose 1 in period 2. Eligible participants from this study continue receiving Dose 1 in the open-label MT10109L-004 study arm 2: The participant pool in this arm are from the MT10109L-002 lead-in study (NCT03785145), who received Placebo in period 1 and MT10109L Dose 2 in period 2. Eligible participants from this study continue receiving Dose 2 in the open-label MT10109L-004 study. arm 3: The participant pool in this arm are from the MT10109L-005 (NCT03721016) and MT10109L-006 (NCT03732833) lead-in studies, who received Placebo in periods 1 \& 2. Eligible participants from this study receives Dose 1 into the GL area and Dose 2 into the LCL area in the open-label MT10109L-004 study. arm 4: The participant pool in this arm are from the MT10109L-001 lead-in study (NCT03795922), who received MT10109L Dose 1 each in period 1 and period 2. Eligible participants from this study continue receiving Dose 1 in the open-label MT10109L-004 study. arm 5: The participant pool in this arm are from the MT10109L-002 lead-in study (NCT03785145), who received MT10109L Dose 2 each in period 1 and period 2. Eligible participants from this study continue receiving Dose 2 in the open-label MT10109L-004 study. arm 6: The participant pool in this arm are from the from MT10109L-005 lead-in study (NCT03721016), who received MT10109L Dose 1 in periods 1 and 2. Eligible participants from this study receives Dose 1 into the GL area and Dose 2 into the LCL area in the open-label MT10109L-004 study. arm 7: The participant pool in this arm are from the MT10109L-006 lead-in study (NCT03732833), who received MT10109L Dose 2 in periods 1 and 2. Eligible participants from this study receives Dose 1 into the GL area and Dose 2 into the LCL area in the open-label MT10109L-004 study. arm 8: The participant pool in this arm are from the MT10109L-005 (NCT03721016) and MT10109L-006 (NCT03732833) lead-in studies, who received MT10109L Dose 1 into GL and Dose 2 into LCL in periods 1 \& 2. Eligible participants from this study receives Dose 1 into the GL area and Dose 2 into the LCL area in the open-label MT10109L-004 study.
Interventions: intervention 1: MT10109L Dose 1 intervention 2: MT10109L Dose 2 intervention 3: MT10109L Dose 1 + Dose 2
Intervention descriptions: intervention 1: MT10109L Dose 1 will be injected into the GL area intervention 2: MT10109L Dose 2 will be injected into the LCL area intervention 3: MT10109L Dose 1 will be injected into the GL area plus MT10109L Dose 2 will be injected into the LCL area

Protocol documents:
Prot_000.pdf: 
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Protocol Title: A Multicenter, Long-term, Open-label Study to Evaluate the Safety of 
MT10109L (NivobotulinumtoxinA) for the Treatment of Glabellar Lines and Lateral Canthal 
Lines
Protocol Number: MT10109L-004
Amendment Number: Amendment 5
Product: MT10109L (NivobotulinumtoxinA)
Brief Protocol Title: MT10109L in the Long-term, Open-label Treatment of Glabellar Lines
and Lateral Canthal Lines
Development Phase: 3
Sponsor Name and Legal Registered Address:
Medytox Inc.
Regulatory Agency Identifying Numbers: IND Number 121473;
EudraCT Number 2014-005303-24
Emergency Telephone Number:
Refer to the study contacts page
SAE Reporting Fax Number/Email:


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Sponsor Signatory:
Refer to the final page of this protocol for signature and date of approval. 


 
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DOCUMENT HISTORY 
Document 
Date 
Amendment 5 
Amendment 4 
June 2022 
October 2019 
Amendment 3 
June 2019 
Amendment 2 
November 2018 
Amendment 1 
September 2018 
Original Protocol 
July 2018 
 
Amendment 5 (June 2022) 
This amendment is considered to be not substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study. 
 
Overall Rationale for the Amendment: 
The overall rationale for the changes implemented in this open-label, extension study was to 
reflect the new study sponsor and safety reporting information,  
 


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1.
1.1.
Protocol Title: A Multicenter, Long-term, Open-label Study to Evaluate the Safety of 
MT10109L (NivobotulinumtoxinA) for the Treatment of Glabellar Lines and Lateral Canthal 
Lines
Protocol Number: MT10109L-004
Brief Title: MT10109L in the Long-term Treatment of Glabellar Lines and Lateral Canthal 
Lines
Study Phase: 3
Study Rationale:
The purpose of this open-label, extension study is to evaluate the long-term safety of repeated
MT10109L treatment of GL and/or LCL in participants with moderate to severe GL, LCL, or 
both (GL and LCL) who completed the lead-in pivotal Phase 3 studies (MT10109L-001, -002,
-005, and -006) over an additional 24 months.
Objectives and Endpoints:
To evaluate the long-term safety of repeat
treatments of MT10109L in participants with 
moderate to severe GL, LCL, or both 
(GL and LCL)
Incidence of adverse events, change from baseline 
in vital sign parameters, and presence of binding 
and neutralizing antibodies
Overall Study Design:


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Number of Participants:
All eligible participants who complete the lead-in pivotal Phase 3 studies (MT10109L-001, -002,
-005, and -006) can enroll in the current study.
Number of Sites:
All sites from the lead-in Phase 3 studies will participate (approximately 44 global sites).
Intervention Groups and Study Duration:


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Data Monitoring Committee: No


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1.2.


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2.
2.1.
The purpose of this open-label, extension study is to evaluate the long-term safety of repeated 
MT10109L treatment of GL and/or LCL in participants with moderate to severe GL, LCL, or 
both (GL and LCL) who completed the lead-in pivotal Phase 3 studies (MT10109L-001, -002,
- 005, and -006) over an additional 24 months.
The clinical development program for MT10109L in the treatment of GL and LCL includes 
4 pivotal Phase 3 double-blind, randomized, parallel-group, placebo-controlled, multicenter 
clinical studies. Each of these studies will provide the primary safety and efficacy data for 
MT10109L treatment of GL (Studies MT10109L-001 and -005) and LCL 
(Studies MT10109L-002 and -006). Participants completing these studies will be eligible to 
enroll into the current 24-month open-label extension study (Study MT10109L-004) and 
continue their treatment of GL, LCL, or both GL and LCL.
2.2.
Glabellar lines are deep furrows or frown lines in the glabellar area of the face and LCL (or CFL) 
are horizontal smile lines by the sides of the eyes. Both types of facial lines result from the 
repetitive functional action of the underlying mimetic facial musculature during animation 
(Blitzer 1993). When injected at therapeutic doses, MT10109L produces partial chemical 
denervation of the muscle, resulting in localized reduction in muscle activity. Because GL and 
LCL result from muscular activity, the muscle relaxation leads to a temporary relief of facial 
lines. While it was previously thought that these facial lines were structural and permanent, the 
effects of these injections demonstrate the lines are part functional and remain because of 
constant muscle tone (Ferreira 2004; Garcia 1996).
The development of facial lines (such as GL and LCL) is an age-related change of the face that 
occurs because of the repetitive muscle contractions that are associated with common facial 
expressions. Thus, these facial lines can be observed with contraction (dynamic rhytides) or in 
more severe cases in repose (static rhytides). Increasing severity in the appearance of facial lines 
has been associated 
self-esteem and sense of well-being (Koblenzer 1996). Furthermore, the appearance of these 


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facial lines can lead to a miscommunication of an emotional state of anger, anxiety, disapproval, 
or sadness (Khan 2001) causing distress and affecting social interactions (Finn 2003).
The popularity of BoNT/A cosmetic treatment of LCL and GL in adults is related to its proven 
efficacy for reducing moderate to severe facial lines (Beer 2006); well documented safety profile 
(Brin 2009); and positive impact on psychological well-being and the resulting psychosocial 
benefits (Finn 2003).
The purpose of this open-label, extension study is to evaluate the long-term safety of repeated 
MT10109L treatment of GL and/or LCL in participants with moderate to severe GL, LCL, or 
both (GL and LCL) who completed the lead-in pivotal Phase 3 studies (MT10109L-001, -002,
- 005, and -006) over an additional 24 months. This information will supplement the primary 
safety and efficacy data from the 4 pivotal lead-in Phase 3 studies. Together with their lead-in
Phase 3 study participation, participants who complete this study will provide up to 3 years of 
continuous treatment exposure data.


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2.3.
Generally, the popularity of BoNT/A cosmetic treatment of GL and LCL in adults is related to its 
proven efficacy for reducing moderate to severe facial lines (Beer 2006); well documented safety 
profile (Brin 2009); and positive impact on psychological well-being and the resulting 
psychosocial benefits (Finn 2003).
In some cases, botulinum toxin effect may be observed beyond the site of local injection. The 
symptoms may include asthenia, generalized muscle weakness, diplopia, eyelid ptosis, 
dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. Swallowing 
and breathing difficulties can be life threatening and there have been reports of death related to 
distant spread of toxin effects with other BoNT/A treatments for noncosmetic indications. The 
risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also 
occur in adults treated for spasticity and other conditions.
Reduced blinking after BoNT/A product injection to the orbicularis muscle can lead to corneal 
exposure, persistent epithelial defect, and corneal ulceration with perforation. In the use of 
another BoNT/A product for treatment of blepharospasm, 1 case of corneal perforation in an 
aphakic eye requiring corneal grafting has occurred because of this effect.


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3.
Primary
To evaluate the 
long-term safety of 
repeat treatments of 
MT10109L in 
participants with 
moderate to severe
GL, LCL, or both 
(GL and LCL)
Incidence of adverse events, change from baseline in vital signs, and presence of binding 
and neutralizing antibodies
Othera
a
There are no objectives associated with the efficacy endpoints in this study.
b
Baseline is from the lead-in studies for all efficacy endpoints in this study. 


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4.
4.1.


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4.2.
MT10109L is a BoNT/A product being developed for IM injection in the treatment of GL and 
LCL. These indications are currently treated with other BoNT/A products. 
This study is designed to assess the 
long-term safety of repeat treatments of MT10109L in the treatment of GL, LCL, or both (GL
and LCL). Efficacy after repeated treatments will also be explored.
4.3.
4.4.
The end of the study is defined as the date of the last scheduled procedure shown in the SoA for 
the last participant in the study globally.
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled procedure shown in the SoA.


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5.
Participants who complete Studies MT10109L-001 (GL), MT10109L-002 (LCL),
MT10109L-005 (GL with or without LCL), and MT10109L-006 (LCL with or without GL) will 
be eligible to enroll into this 24-month open-label extension study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.


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5.3.
No restrictions are required.
5.4.
.


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6.
Study intervention is defined as any investigational intervention(s), marketed product(s), or
placebo intended to be administered to a study participant according to the study protocol.
Retreatment criteria are described in Section 6.6.


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6.1.2.
Only trained and medically qualified physicians experienced with BoNT/A injections are 
authorized to administer the study interventions. 


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The GL study interventions will be administered as IM injections at 5 injection sites in the 
glabellar complex, 2 in each corrugator muscle and 1 in the procerus (Figure 6-1 A). The LCL 
study interventions will be administered as bilaterally symmetrical IM injections at 3 injection 
sites in the lateral aspect of each orbicularis oculi (Figure 6-2 A). When GL and LCL are treated 
together, the appropriate injection technique for each area will be followed, as described below.
Participants must be observed for adverse events for 
30 minutes after each study intervention
injection.
Glabellar Line Injection Technique


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GL and LCL Participants
GL and LCL will be treated together, following the appropriate injection technique for each area, 
as described above.
6.2.
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention, and only authorized 
site personnel may administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
personnel.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions are 
provided in the study manual.
All unused study intervention and empty vials must be returned to the sponsor at the termination 
of the study. Unit counts will be performed when the study intervention is returned, and all study 
intervention must be accounted for. Unused drug supplies and empty vials will be returned to the 
sponsor.
6.3.
This is an open-label study. 
The participant s identification number from the lead-in Phase 3 study will be used in this 
extension study. This will serve as the participant identification number on all study documents.
.


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6.4.
Participants will receive all doses under the direct supervision of study site personnel. Study 
intervention compliance will not be calculated.
The study site will keep an accurate drug disposition record that specifies the amount of study 
intervention administered to each participant and the date of administration.
6.5.
The use of any concomitant medication or vaccine (including prescription or over-the-counter
medication, vitamins, and/or herbal supplements)
CRF at 
each visit along with the reason the medication is taken.
At each study visit, study site personnel will question each participant specifically on the use of 
concomitant medications. Study site personnel must notify the sponsor immediately if a 
participant consumes any concomitant medications not permitted by the protocol. Participants
who admit to using prohibited concomitant medications may be discontinued from the study at 
the discretion of the investigator or sponsor.


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6.5.2.
Any medication or vaccine (including prescription or over-the-counter medication, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:
investigator. If the permissibility of a specific medication/intervention is in question, please 
contact the sponsor.
The sponsor must be contacted if there are any questions regarding concomitant or prior therapy.
Any medication taken during the study between the date of the first dose of study intervention 
and the date of the end-of-study visit will be recorded in the eCRF as a concomitant medication; 
any medication started after the end-of-study visit will not be considered a concomitant 
medication and should not be captured in the eCRF.
6.5.3.
Rescue medicine is not applicable.
6.6.
This protocol does not allow for alteration from the currently outlined dosing schedule.
Participants entering from the lead-in Phase 3 studies will receive open-label study intervention
based on meeting retreatment criteria.


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6.7.
There is no further intervention following the end of the study.


 
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7. 
A premature discontinuation will occur if a participant who signs the ICF ceases participation in 
the study, regardless of circumstances, before the completion of the protocol-defined study 
procedures.  
Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented on the appropriate 
eCRF. 
Definitions of the standard terms are provided in Appendix 5. 
Reasons for discontinuation from the study intervention and/or the study may include the 
following commonly used terms: 
 
Adverse event 
Lost to follow-up 
Lack of efficacy 
Other 
Physician decision 
Pregnancy 
Protocol deviation 
Site terminated by sponsor 
Study terminated by sponsor 
Withdrawal by subject 
 
7.1. 
Study intervention must be discontinued for the following reasons: 
 Pregnancy (see Appendix 7 and Section 8.3.5. Pregnancy) 
 Other safety criteria (eg, hypersensitivity to the study intervention, failure to continue to meet 
study entry criteria) 
Women who test positive for urine pregnancy test will NOT receive further interventions and 
will be discontinued from the study. They must complete study exit procedures and be followed 
up for pregnancy outcome. See the SoA for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 


 
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7.2. 
 A participant may withdraw from the study at any time at his/her own requestor may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons. 
 If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
 See the SoA for data to be collected at the time of study discontinuation and follow-up and 
for any further evaluations that need to be completed. 
7.3. 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the study site for a required 
study visit: 
 The study site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
 Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant
methods). These contact attempts will be documented in the participant
. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 


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8.
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns must be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All assessments must be completed after the participant removes their make-up (if wearing 
any) and before administration of study intervention. 


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8.2.
Planned timepoints for all safety assessments are provided in the SoA.
8.2.1.
The investigator will question the participant to ascertain whether any adverse events were 
experienced since the previous visit. Additionally, at treatment visits, the participants will be 
observed for 
30 minutes following study intervention. All pertinent information regarding 
adverse events (ie, date of onset and stop, duration, outcome, severity, relationship to study 
intervention, action or treatment required) will be obtained and recorded in the source documents 
and appropriate eCRF page.
8.2.2.
Pulse rate (beats per minute): Participants are to be seated for at least 2 minutes, and pulse 
rate will be counted over 60 seconds and recorded in the source document and eCRF as 
beats per minute.
Blood pressure (mm Hg): Participants are to be seated for at least 2 minutes, and 
systolic/diastolic blood pressure will be measured.
Respiration rate (breaths per minute): Participants are to be seated for at least 2 minutes, and 
breaths will be counted for 30 seconds and multiplied by 2.


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8.2.3.
Urine dipstick kits will be used to conduct pregnancy tests at the timepoints specified in the SoA,
or more fre
discretion.
8.2.4.
Suicidal risk monitoring is not applicable for this study.
8.3.
The definitions of an adverse event or SAE can be found in Appendix 3.
Adverse events will be reported by the participant.
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an adverse event or SAE and remain responsible for 
following up adverse events that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention (see Section 7).
The following expected adverse drug reactions are based on BOTOX clinical trial data for the 
treatment of GL and LCL (Tables 8-1 and 8-2, respectively).
Table 8-1
Expected Adverse Reactions for Treatment of Glabellar Lines
Expected Adverse Reactionsa
Incidence
Eyelid ptosis 
3%
Facial pain
1%
Facial paresis
1%
Muscular weakness
1%
a Data are based on BOTOX glabellar lines clinical trial data (BOTOX Cosmetic US Package Insert, 2017)
Table 8-2
Expected Adverse Reactions for Treatment of Lateral Canthal Lines
Expected Adverse Reactionsa
Incidence
Eyelid oedema 
1%
a Data are based on BOTOX lateral canthal lines clinical trial data (BOTOX Cosmetic US Package Insert, 2017)
The adverse drug reactions of eyelid edema, eyelid ptosis, facial pain, facial paresis, and 
muscular weakness with BOTOX are usually mild in severity, reversible, and have a low 


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incidence. Therefore, no treatment for these reactions is recommended. If these reactions are 
moderate or severe, medical help should be sought as needed.
8.3.1.
All adverse events will be collected from the signing of the ICF at the timepoints specified in the 
SoA (Section 1.3), and as observed or reported spontaneously by study participants until 30 days 
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent will be recorded in the adverse event section of the eCRF.
All SAEs will be collected from the signing of the ICF study at the timepoints specified in the 
SoA (Section 1.3), and as observed or reported spontaneously by study participants, until at least 
12 weeks after the 
last administration of MT10109L intervention. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek adverse event or SAE information after 
conclusion of the study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she considers 
the event to be reasonably related to the study intervention or study participation, the investigator 
must promptly notify the sponsor.
The method of recording, evaluating, and assessing causality of adverse events and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
8.3.2.
Care will be taken not to introduce bias when detecting adverse events and/or SAEs. Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire about 
adverse event occurrences.
8.3.3.
After the initial adverse event/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All TEAEs including SAEs, AESIs (Section 8.3.6), and 
TEAEs that lead to study discontinuation will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3).


 
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The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the adverse event or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any postmortem findings including 
histopathology. 
New or updated information will be recorded in the originally completed eCRF. 
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information. 
8.3.4. 
 Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.  
 The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/IECs, and investigators.  
 Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
 An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the 
ochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.3.5. 
 Urine pregnancy testing will be conducted for women of childbearing potential prior to each 
study intervention and at the study exit visit. See Appendix 7 for detailed information on 
definition of women of childbearing potential, use of contraceptives, and pregnancy. 
 To minimize the risk of pregnancy, all women of childbearing potential must agree to use a 
highly effective or acceptable contraception method (Appendix 7) consistently and correctly 
throughout the duration of the study. For participants of childbearing potential in Germany 
and Belgium, only highly effective contraception methods are allowed for this study. 
 Women who test positive for urine pregnancy test will NOT receive further intervention and 
will be discontinued from the study.  


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Women who test positive for urine pregnancy test must complete end-of-study procedures 
and be followed up for pregnancy outcome.
Any termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 7.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) or genetic abnormalities (whether leading to an elective 
abortion or not) are considered SAEs.
8.3.7.
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows:
Wrong study intervention
Wrong dose (including dosing regimen, strength, form, concentration, amount)
Wrong route of administration
Wrong participant (ie, not administered to the intended participant)
Medication errors include occurrences of overdose and underdose of the study intervention.
Overdose: Unintentional administration of a quantity of the study intervention given per 
administration or per day that is above the maximum recommended dose according to the 
reference safety information or protocol for the study intervention or comparator as applicable. 
See Section 8.4 for information on the treatment of overdose. 
Underdose: Unintentional administration of a quantity of the study intervention given per 
administration or per day that is under the minimum recommended dose according to the 
protocol. 


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8.4.
Overdose of MT10109L is a relative term and depends upon dose, site of injection, and 
underlying tissue properties. Signs and symptoms of overdose are likely not to be apparent 
immediately postinjection. Excessive doses may produce local, or distant, generalized and 
profound neuromuscular paralysis.
Because MT10109L is administered as injections by physicians, for this study, the chance of 
overdose is extremely low. Should accidental injection or oral ingestion occur, or overdose be 
suspected, the participant should be medically monitored for up to several weeks for progressive 
signs or symptoms of systemic muscular weakness that could be local or distant from the site of 
injection, which may include ptosis, diplopia, dysphagia, dysarthria, generalized weakness, or 
respiratory failure. For GL or LCL, eyelid ptosis, diplopia, and vision blurred are known local 
effects of the toxin. These participants should be considered for further medical evaluation and 
appropriate medical therapy immediately instituted, which may include hospitalization.
If the musculature of the oropharynx and esophagus is affected, aspiration may occur, which may 
lead to development of aspiration pneumonia. If the respiratory muscles become paralyzed or 
sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes 
place. Supportive care could involve the need for a tracheostomy and/or prolonged mechanical 
ventilation, in addition to other general supportive care.
In the event of an overdose, the investigator should educate the participant, monitor the course of 
overdose, contact the MSP as needed, document the quantity of the excess dose, associated 
adverse events as well as the duration of the overdose in the eCRF.
8.5.
Pharmacokinetic parameters are not evaluated in this study.
8.6.
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics are not evaluated in this study.
8.8.
Immunogenicity Assessments
The presence of antidrug antibodies, including binding antibodies and neutralizing antibodies to 
MT10109L, will be assessed during the course of the study using validated assays.


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A 2-stage assay approach will be used for the detection of binding antibodies against MT10109L 
will be screened for the presence of binding antibodies using the validated ELISA in a 3-tier 
format (screening, confirmation, and titering). The screen positive serum samples will be 
subsequently immunodepleted to confirm that the binding antibodies are specific to MT10109L
and titered to assess the extent of antibodies present. In Stage 2, only samples that are confirmed 
positive in the ELISA will be tested for neutralizing antibodies to MT10109L.
8.9.
Medical resource utilization and health economics parameters are not evaluated in this study.


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9.
9.1.
Not applicable.
9.2.
For this long-term follow-up study, no formal statistical power/sample size calculation was used. 
Approximately 800 participants are anticipated to be enrolled into this study. 
9.3.
9.4.
The SAP will be developed and finalized before database lock and will describe the participant 
populations to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. This section is a summary of the planned statistical analyses of the efficacy
endpoints.


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9.4.2.
The safety parameters will include:
Adverse events
Vital signs
Immunogenicity analyses
.
An adverse event that occurs more than 30 days after study exit will not be counted as a TEAE.
An adverse event will be considered a TESAE if it is a TEAE that additionally meets any SAE 
criteria.
The number and percentage of participants reporting TEAEs in each study intervention group 
will be tabulated by system organ class and preferred term and by system organ class, preferred 
term, and severity
.
The number and percentage of participants reporting treatment-related TEAEs in each study 
intervention group will be tabulated by system organ class and preferred term by MT10109L
cycle.
If more than 1 adverse event is coded to the same preferred term for the same participant, the 
participant will be counted only once for that preferred term using the most severe and most 
related occurrence for the summarizations by severity and by relationship to MT10109L
intervention.


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Summary tables will be provided for participants with SAEs and participants with adverse events
leading to discontinuation if 5 or more participants reported such events. Listings of all adverse 
events, SAEs, and adverse events leading to discontinuation by participant will be presented.
The definitions of an adverse event and SAE can be found in Appendix 3.
Descriptive summaries (n, mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for vital signs (systolic and diastolic blood pressure,
pulse and respiration rate). These summaries will be presented by study intervention for each 
intervention and by visit.
9.4.3.
Immunogenicity results, manifested as the presence of binding antibodies and neutralizing 
antibodies to MT10109L, will be summarized in a table.
9.5.


 
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10. 
10.1. 
10.1.1. 
 This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines 
 Applicable ICH/ISO GCP guidelines 
 Applicable laws and regulations 
 The protocol, protocol amendments, ICF, 
rochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
 Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
 The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
 Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, the 
IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable) 
10.1.2. 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 


 
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10.1.3. 
 The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.  
 Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representatives will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, where applicable, and the IRB/IEC or study center.  
 The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
 Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study.  
 
authorized representative.  
10.1.4. 
 Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred.  
 The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.  
 The participant must be informed that his/her medical records may be examined by clinical 
quality assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
 Study data and information may be published in nonpromotional, peer-reviewed publications 
either by or on behalf of the sponsor.  
 Clinical study reports, safety updates, and annual reports will be provided to regulatory 
authorities as required. 
 Company-sponsored study information and tabular study results will be posted on the US 
www.ClinicalTrials.gov and other publicly accessible 
sites. 


 
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10.1.6. 
 All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.  
 The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
 The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
 The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
 Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator as stated in the clinical trial agreement. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.  
10.1.7. 
 Source documents provide evidence for the existence of the participant and substantiate the 
 
 Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study.  
 Definition of what constitutes source data can be found in Section 4.0 of ICH E6, Good 
Clinical Practice: Consolidated Guidance and must follow ALCOA, ie, records must be 
attributable, legible, contemporaneous, original, and accurate.  
10.1.8. 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 


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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor s procedures, or GCP guidelines
Inadequate recruitment of participants by the investigator
Discontinuation of further study intervention development
10.1.10.
The investigator is responsible for compliance with the protocol at the investigational site and 
ensure the availability of appropriate study personnel and compliance with GCP regulations and 
procedures. Trainings are provided by the sponsor to discuss the protocol procedures and study 
requirements. A representative of the sponsor will make frequent contact with the investigator 
and his/her research staff and will conduct regular monitoring visits at the site to review 
participant and study intervention accountability records for compliance with the protocol. 
Protocol deviations will be discussed with the investigator upon identification. The use of the 
data collected for the participant will be discussed to determine if the data are to be included in 
the analysis. The investigator will enter data that may be excluded from analysis as defined by 
the protocol deviation specifications. Significant protocol deviations will be reported to the 
IRB/IEC according to the IRB/I


 
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10.2. 
Not applicable. 


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10.3.
10.3.1.
AE Definition
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study intervention.
.
Events Meeting the AE Definition 
Any abnormal safety assessments (eg, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (ie, not related to progression of underlying disease); for 
example:
The test result is associated with accompanying symptoms, and/or
The test result requires additional diagnostic testing or medical/surgical intervention, 
and/or


 
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 The test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy, and/or 
 The test result is considered to be an AE by the investigator or sponsor. 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
 
New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an AE 
or SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 
Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AEs or SAEs if they fulfil the definition of an AE or SAE.  
 
Events NOT Meeting the AE Definition  
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Merely 
repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not 
require recording as an AE. 
 
The disease/disorder being studied or expected progression, signs, or symptoms (clearly 
defined) of the disease/disorder being studied, unless more severe than expected for the 
 
 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 


 
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10.3.2. 
SAEs must meet both the AE criteria described above and the seriousness criteria listed below. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life threatening 
The term life threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or intervention 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective intervention of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 
life functions. 
 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 


 
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f. 
Other situations: 
 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
Examples of such events include invasive or malignant cancers, intensive intervention in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
10.3.3. 
AE and SAE Recording 
 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 
The investigator will then record all relevant AE or SAE information in the eCRF. 
 
It is not 
records to the sponsor in lieu of completion of the AE or SAE eCRF page. 
 
There may be instances when copies of medical records for certain cases are requested by 
the sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
sponsor. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 


 
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Assessment of Intensity 
MILD 
A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 
MODERATE 
A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
research participant. 
SEVERE 
A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
An event is defined as serious when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE or SAE. 
 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 
The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment. 
 
For each AE or SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE or SAE and has provided an assessment of causality. 
 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the sponsor. 
 
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 


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The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
See Section 8.3.3
10.3.4.
SAE Reporting
In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE form, sent by overnight mail or courier service.
Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE form within the designated reporting time frames.


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10.4.
AE
adverse event 
AESI
adverse event of special interest
ANCOVA
analysis of covariance
BoNT/A
botulinum toxin type A
CFL
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
DVD
digital versatile disc
ECG
electrocardiogram
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EU
European Union
FDA
US Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GL
glabellar lines
HIPAA
Health Insurance Portability and Accountability Act
HRT
hormonal replacement therapy
IB
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
institutional ethics committee
IM
intramuscular
IND
investigational new drug application
IRB
institutional review board


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ISO
International Organization for Standardization
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IWRS
interactive web response system
LCL
lateral canthal lines
LD50
median lethal intraperitoneal dose
MSP
medical safety physician
PRO
patient-reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reactions
TCA
trichloroacetic acid
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent SAE
U
unit
UFL
upper facial lines
US
United States
WOCBP
woman of childbearing potential


 
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10.5. 
 
 
Adverse event 
Any untoward medical occurrence in a participant 
or clinical investigation subject administered a 
pharmaceutical product and which does not 
necessarily have a causal relationship with this 
treatment. An AE can therefore be any unintended 
sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, 
whether or not related to the medicinal 
(investigational) product. For further information, 
see the ICH Guideline for Clinical Safety Data 
Management: Definitions and Standards for 
Expedited Reporting (modified from ICH E2A) 
Synonyms: side effect, adverse experience. See 
also serious adverse event, serious adverse 
experience. (CDISC glossary) 
Completed 
To possess every necessary or normal part or 
component or step; having come or been brought 
to a conclusion (NCI) 
Death 
The absence of life or state of being dead (NCI) 
Disease relapse 
The return of a disease after a period of remission 
Failure to meet randomization criteria 
An indication that the subject has been unable to 
fulfill/satisfy the criteria required for assignment 
into a randomized group 
Lack of efficacy 
The lack of expected or desired effect related to a 
therapy (NCI) 
Lost to follow-up 
The loss or lack of continuation of a subject to 
follow-up 
Non-compliance with study drug 
An indication that a subject has not agreed with or 
followed the instructions related to the study 
medication (NCI) 
Other 
Different than the one(s) previously specified or 
mentioned (NCI) 
Physician decision 
A position, opinion or judgment reached after 
consideration by a physician with reference to 
subject (NCI) 
Pregnancy 
Pregnancy is the state or condition of having a 
developing embryo or fetus in the body (uterus), 
after union of an ovum and spermatozoon, during 
the period from conception to birth. (NCI) 
Progressive disease 
A disease process that is increasing in extent or 
severity (NCI) 


 
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Protocol deviation 
An event or decision that stands in contrast to the 
guidelines set out by the protocol (NCI) 
Recovery 
A healing process and/or an outcome implying 
relative health. The term is typically used in the 
context of direct and indirect effects of sickness 
or injury. (NCI) 
Screen failure 
The potential subject who does not meet one or 
more criteria required for participation in a trial 
Site terminated by sponsor 
An indication that a clinical study was stopped at 
a particular site by its sponsor (NCI) 
Study terminated by sponsor 
An indication that a clinical study was stopped by 
its sponsor (NCI) 
Technical problems 
A problem with some technical aspect of a 
clinical study, usually related to an instrument 
(NCI) 
Withdrawal by parent/guardian 
An indication that a study participant has been 
removed from the study by the parent or legal 
guardian 
Withdrawal by subject 
An indication that a study participant has 
removed itself from the study (NCI) 
 


 
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10.6. 
Parameter Group 
Parameter 
Value 
Trial information 
Trial Title 
A Multicenter, Long-term, Open-label 
Study to Evaluate the Safety of 
MT10109L (NivobotulinumtoxinA) for 
the Treatment of Glabellar Lines and 
Lateral Canthal Lines 
 
Clinical Study Sponsor 
Medytox, Inc.  
 
Trial Phase Classification 
Phase 3 
 
Trial Indication 
Glabellar Lines and Lateral Canthal Lines 
 
Trial Indication Type 
Intervention 
 
Trial Type 
Safety 
 
Trial Length 
Approximately 24 months  
 
Planned Country of Investigational Sites 
United States, Canada, European Union, 
and Russia 
 
Planned Number of Participants 
Approximately 800 participants 
 
FDA-Regulated Device Study 
No 
FDA-Regulated Drug Study 
Yes
Pediatric Study
No
Participant 
information 
Diagnosis Group 
Participants who completed lead-in 
Phase 3 studies MT10109L-001 (GL), 
MT10109L-002 (LCL), MT10109L-005 
(GL with or without LCL), and 
MT10109L-006 (LCL with or without 
GL) 
Healthy Participant Indicator
No
Planned Minimum Age of Participants
19
 
Planned Maximum Age of Participants 
Not applicable 
(66 years of age for studies in Russia)
Sex of Participants 
Both
Stable Disease Minimum Duration
Not applicable


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Parameter Group
Parameter
Value
Interventions
Investigational Therapy or Intervention
MT10109L (NivobotulinumtoxinA)
Intervention Type
Drug
Pharmacological Class of Invest. Therapy
NivobotulinumtoxinA
Dose Units
4 U per 0.1 mL
Dosing Frequency
Up to 9 interventions
Route of Administration
Intramuscular
Current Therapy or Intervention
Not applicable
Added on to Existing Interventions
No
Control Type
None
Comparative Intervention Name
Not applicable
Trial design
Study Type
Interventional
Intervention Model
Open-label
Planned Number of Arms
3
Trial is Randomized
No
Randomization Quotient
Not applicable
Trial Blinding Schema
Open-label
Stratification Factor
Not applicable
Adaptive Design
No
Study Stop Rules
Not applicable


 
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10.7. 
10.7.1. 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
 Females on HRT and whose menopausal status is in doubt will be required to continue to 
use one of the nonestrogen hormonal highly effective contraception methods from the 
lead-in study if they wish to continue their HRT during the current study.  


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10.7.2.
Female Participants
Table 10-1
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of < 1% per year when used consistently and correctly
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
Oral 
Intravaginal 
Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation
Oral 
Injectable 
Highly Effective Methods That Are User Independenta
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation
IUD
IUS
Etonogestrel implant (ie, Nexplanon®)
Bilateral tubal occlusion
Intrauterine copper contraceptive (ie, ParaGard®)
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
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Table 10-2
Acceptable Contraceptive Methods
Acceptable birth control methods that result in a failure of more than 1% per year include:
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action
Male or female condom with or without spermicide 
Cap, diaphragm, or sponge with spermicide
Nonhormonal intrauterine device
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) 
are also considered acceptable, but not highly effective, birth control methods.
10.7.3.
Pregnancy testing, with a sensitivity of 
 will be performed according to 
instructions provided in the pregnancy test kit.
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine pregnancy test at Day 1 and, if a participant meets retreatment criteria, a
negative urine pregnancy test prior to retreatment.
Additional pregnancy testing is not required during the study intervention period.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.
10.7.4.
Female Participants Who Become Pregnant 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital abnormalities, ectopic pregnancy) or genetic 
abnormalities (whether leading to an elective abortion or not) are always considered to be an 
SAE and will be reported as such. Any poststudy pregnancy-related SAE considered 
reasonably related to the study intervention by the investigator will be reported to the 


 
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sponsor as described in Section 8.3.4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study. 


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11. 
Beer KR. Comparative evaluation of the safety and efficacy of botulinum toxin type A and 
topical creams for treating moderate-to-severe glabellar rhytids. Dermatol Surg. 
2006;32:184-192. 
Blitzer A, Brin MF, Keen MS, Aviv JE. Botulinum toxin for the treatment of hyperfunctional 
lines of the face. Arch Otolaryngol Head Neck Surg. 1993;119:1018-1022. 
BOTOX® Cosmetic (onabotulinumtoxinA) for injection [package insert]. Irvine, CA: Allergan, 
Inc; October 2017. 
Brin MF, Boodhoo TI, Pogoda JM, James LM, Demos G, Terashima Y, et al. Safety and 
tolerability of onabotulinumtoxinA in the treatment of facial lines: A meta-analysis of individual 
patient data from global clinical registration studies in 1678 participants. J Am Acad Dermatol. 
2009;61:961-970.e1-11. 
Ferreira MC, Salles AG, Gimenez R, Soares MFD. Complications with the use of botulinum 
toxin type A in facial rejuvenation: report of 8 cases. Aesthet Plast Surg. 2004;28:441-444. 
Finn CJ, Cox SE, Earl ML. Social implications of hyperfunctional facial lines. Dermatol Surg. 
2003;29:450-455.Garcia A,  
Garcia A, Fulton JE Jr. Cosmetic denervation of the muscles of facial expression with botulinum 
toxin: A dose-response study. Dermatol Surg. 1996;22:39-43.  
Khan JA. Aesthetic surgery: Diagnosing and healing the miscues of human facial expression. 
Ophthal Plastic Reconstr Surg. 2001;17:4-6. 
Koblenzer CS. Psychologic aspects of aging and the skin. Clin Dermatol. 1996;14:171-177. 
 
 
 
 
 
 
 
 



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Table of Contents 
 


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1. 
Introduction 
Study MT10109L-004 is an open-label extension of Studies MT10109L-001, -002, -005, 
and -006 evaluating long term safety of MT10109L. This statistical analysis plan provides an 
expanded and detailed description of the statistical methods presented in the most recent 
 
 
All safety and efficacy analyses will be integrated analyses that include data from all the 
preceding pivotal studies (MT10109L-001, -002, -005, and -006) and the extension study 
(MT10109L-004). Participants can receive up to 3 interventions in the lead-in studies. Data from 
up to 3 treatment cycles in the preceding studies and data from the treatment cycles in the -004 
extension study will be analyzed as outlined in this analysis plan. All participants enrolled in 
Study MT10109L-004 will be included for analysis, whether they receive study intervention or 
not. Specifications of tables, figures, and data listings are contained in a separate document. 
1.1. 
Objectives and Endpoints 
Table 1-1 
Objectives and Endpoints 
 
Objective 
Clinical 
Category 
Statistical 
Category 
Estimand/Variable 
Primary Objective: To evaluate the long-term safety of repeat treatments of MT10109L in participants 
with moderate to severe GL, LCL, or both GL and LCL 
Safety: 
Incidence of 
adverse 
events 
Primary 
• 
Variable: Presence of TEAEs 
• 
Population: ITT 
• 
Analysis: Categorical descriptive 
• 
Number and percentage of participants in individual 
categories 
o 
Participants with ≥ 1qualifying event counted once 
per individual category 
Safety: 
Vital signs 
Primary 
• 
Variable: Change from baseline in vital signs at each cycle 
after intervention and end of study 
• 
Population: ITT 
• 
Analysis: Continuous descriptive for baseline, postbaseline, 
and change from baseline values 
N1 = participants with nonmissing values at both baseline and the 
specified postbaseline analysis visit/timepoint 
Safety: 
Primary 
• 
Presence of binding and neutralizing antibodies 
Binding and 
• 
Population: ITT 
neutralizing 
• 
Analysis: Categorical descriptive 
antibodies 


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1.2. 
Study Design 
Overall Study Design: 
• Global, multicenter, open-label, repeat treatment, parallel-group 
• Treatment Group: MT10109L 
 administered in the same treatment 
area(s) with the same number of injections and injection sites as in their lead-in Phase 3 
study. 
• Study Duration: 24-month treatment period 
• Participants ≥ 19 years old who completed Studies MT10109L-001 (GL), 
MT10109L-002 (LCL), MT10109L-005 (GL with or without LCL), and MT10109L-006 
(LCL with or without GL) and meet study entry criteria may receive up to 9 study 
interventions in Study MT10109L-004 
• Approximately 800 participants will be enrolled at approximately 44 global sites 
 
 
 
• Based on meeting retreatment criteria for each intervention, the first intervention in this 
study may occur at the Day 1 visit and the last intervention may occur at the Day 690 
visit (30 days prior to Day 720/study exit). 
• 
 
 
 
 
• Participants who complete this study will have an exit visit on Day 720. 
 
 
 
 
 
 
 
 
 
 
 
 


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• Adverse events (AEs) will be monitored in-clinic for ≥ 30 minutes after each study 
intervention,
 at each 
subsequent scheduled in-clinic or telephone visit, and at any other time an AE is reported. 
• 
 
 
 
 
 


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2. 
Sample Size Determination 
For this long-term follow-up study, no formal statistical power/sample size calculation was used. 
Approximately 800 participants are anticipated to be rolled-over into this study. This number is 
estimated from the sample size from the lead-in Phase 3 studies (MT10109L-001, -002, -005, 
and -006);
 
 
 
 


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3. 
Statistical Hypotheses 
Not applicable. 




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5. 
Statistical Analyses 
5.1. 
General Considerations 
. 
The proportions of participants who achieve the efficacy endpoints will be summarized with 
frequency tables. The 95% CI for responders will be estimated based on the observed data by 
intervention group and by treatment cycle. For the US FDA, efficacy analyses will be based on 
the ITT population.
 
 
The safety analyses will be based on the ITT population.  
Statistical analyses will be performed using version 9.4 (or newer) of statistical analysis software 
(SAS) on a Linux operating system. 
 




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In general, there will be no substitution of missing time or date. However, any partial 
information will be utilized to its full extent wherever sensible. For example, a medication may 
be classified as a prestudy medication if the partial information of the medication ending date 
with only month and year permits a determination that the medication ended prior to the 
injection date of the study intervention. 
5.1.4. 
Descriptive Statistics 
Data will be summarized with descriptive statistics and/or response frequencies. Descriptive 
statistics for continuous variables include the sample size (N), mean, standard deviation (SD), 
median, minimum (Min), and maximum (Max). Descriptive statistics for categorical variables 
include the sample size (N) and frequency (counts and percentages). 
5.1.5. 
Significance Level and Confidence Intervals 
The level of significance used for all statistical tests will be 0.05, 2-sided, unless stated 
otherwise. 
For all endpoints for which confidence intervals are calculated, the following methods of 
calculation apply, unless otherwise stated. 
For dichotomous variables, 2-sided 95% confidence intervals for proportions will be calculated 
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5.1.6. 
Dictionaries 
The Medical Dictionary for Regulatory Activities (MedDRA Version 24.1) will be used to code 
AEs, medical history, and procedures. MedDRA primary system organ class (SOC), MedDRA 
high level term (HLT), together with the drug record number and base preferred drug name from 
the enhanced version of World Health Organization Drug Dictionary (WHO DDE) Global 
March 2021, will be used to classify all medications (ie, prior or concomitant) recorded in the 
study. Base preferred name is the WHO DDE drug preferred name assigned to the 11-digit code 
of drug record number+01+001. 
5.1.7. 
Units 
Metric system units will be used; degrees Celsius for temperature, kilograms (kg) for body 
weight, and centimeters (cm) for height. 
5.1.8. 
Investigator Sites 
The site number for Studies MT10109L-001, -002, -005, or -006 will be used for all tables and 
listings. 
5.1.9. 
Study Intervention  
If “Was the subject injected per protocol?” ticked as yes, the dose used of each injection will 
follow per protocol section 6.1.2 in extension period. 
5.2. 
Participant Dispositions 
5.2.1. 
Disposition and Exit Status 
The analysis will be performed using the ITT 
populations for overall study and by 
treatment cycle. The lead-in and extension study possible treatment regimens will be used. 
The disposition of study participants consists of a summary of the number of participants 
enrolled and available in the ITT 
 populations by treatment regimen and overall.
 
 
 
Tabulation of the numbers and percentages of participants in each exit status category (ie, AE, 
pregnancy, lost to follow-up, lack of efficacy, withdrawal by subject, physician decision, death, 
progressive disease, protocol deviation, noncompliance with study drug, study terminated by 
sponsor, site terminated by sponsor and other) will be provided for each treatment regimen of 
each treatment cycle. Discontinued participants will be listed along with the corresponding 
reason(s) for early withdrawal from the study. 
5.3. 
Primary Endpoints Analysis 
The primary endpoints are incidence of AEs, change from baseline in vital sign parameters, and 
presence of binding and neutralizing antibodies for safety. 


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5.3.1. 
Definition of Endpoints 
5.3.1.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence in a participant or clinical investigation 
participant administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment. 
 
 
 
 
 
 
 
. 
 
 
 
 
 
Per case report form instructions, a new AE record will be created with a new AE onset date for 
any AE that worsens. Therefore, TEAEs can simply be identified as those AEs with recorded 
onset date on or after the date of the first study intervention and within 30 days after the study 
exit. 
An AE will be considered a treatment-emergent serious adverse event (TESAE) if it is a TEAE 
that additionally meets any serious adverse event (SAE) criteria. 
A SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, 
a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered a SAE when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. All cancer AEs are considered SAEs by Allergan. Abnormal 
pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) or genetic abnormalities (whether leading to an elective abortion or not) are 
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5.3.1.2. 
Vital Signs 
Vital sign measurements are pulse rate (beats per minute), respiration rate (breaths per minute), 
and blood pressure (mm Hg). Participants are to be seated for at least 2 minutes before 
measurements are collected 
 
 
5.3.1.3. 
Immunogenicity Analyses 
Blood samples for immunogenicity testing will be collected from each participant
 
 
  
5.3.2. 
Main Analytical Approach 
5.3.2.1. 
Adverse Events 
Adverse events will be coded from the verbatim text into preferred term (PT) and SOC by using 
the MedDRA dictionary.
 
 
 
 
 
. 
 
 
 
 
For an ongoing AE from the preceding Studies MT10109L-001, -002, -005 and -006 to extension 
Study MT10109L-004, the onset date, PT, and onset severity will be used to match the same 
ongoing AE from different studies. 
The incidence of AEs will be summarized with frequencies (counts and percentages) by 
treatment regimen for all events regardless of causality, for all SAEs regardless of causality, and 
for treatment-related AEs (those with a reasonable possibility of being caused by the study 
intervention in the investigator’s opinion). 
The incidence of AEs for all, SAEs (see Section 5.3.1 for definition), and treatment-related AEs 
will be presented and summarized by MT10109L cycle and over the entire study as follows 
unless otherwise specified: 
1. Overall incidence of TEAEs: 


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This summary will include the incidence of all TEAEs, the incidence of TEAEs related to 
treatment, the incidence of TESAEs, the incidence of TESAEs related to treatment, the 
incidence of TESAEs not-related to treatment, AEs that lead to study discontinuation, and 
death. 
2. By PT within primary SOC: 
This summary will present the incidence of each PT within the primary SOC, as well as the 
overall primary SOC incidence. Primary SOCs will appear alphabetically, and PTs within each 
SOC will be sorted by descending incidence. A participant with multiple events coding to the 
same PT within a primary SOC will be counted only once for the PT within that primary SOC. 
3. By maximum severity of PT within primary SOC: 
For all TEAEs, a summary will present the incidence of the maximum severity of each PT within 
a primary SOC for the entire study only. Primary SOCs will appear alphabetically, and PTs 
within each SOC will be sorted by descending incidence. For a given AE, if more than one 
severity grade is reported for a given participant, the worse severity grade will be included in the 
tabulation. If a participant has multiple events coding to the same PT within a primary SOC, the 
maximum severity for that participant will be used, and that participant will be counted only 
once for that PT within that primary SOC. This summary will be presented and summarized by 
MT10109L cycle only. 
4. TEAEs leading to discontinuation by PT within primary SOC: 
This summary will present the incidence of each PT within the primary SOC, as well as the 
overall primary SOC incidence for AEs leading to premature discontinuation from the study.  
All AEs will be presented in a by-subject listing, detailing the lead-in/extension treatment, first 
treatment date, treatment cycle of AE, treatment date for corresponding treatment cycle, 
verbatim term, the preferred term (PT), system organ class (SOC), location of event, start 
date/day (number of days since Studies MT10109L-001, -002, -005, and -006 Day 1), end 
date/day (number of days since Studies MT10109L-001, -002, -005, and -006 Day 1), TEAE or 
not, severity, outcome, relationship to study treatment, relationship to study procedure, 
, action taken to study treatment, action taken to 
study procedure, serious adverse event criteria and leading to discontinuation. 
 
 
 
 
 


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5.3.2.2. 
Vital Signs 
Descriptive summaries (n, mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for vital signs (systolic and diastolic blood pressure, 
pulse, and respiration rate). These summaries will be presented by study intervention for each 
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5.3.2.3. 
Immunogenicity Analyses 
A 2-stage assay approach will be used for the detection of binding antibodies against MT10109L 
and neutralizing antibodies against MT10109L in participants’ serum. In Stage 1, serum samples 
will be screened for the presence of binding antibodies using the validated enzyme-linked 
immunosorbent assay (ELISA) in a 3-tier format (screening, confirmation, and titering). The 
screen positive serum samples will be subsequently immunodepleted to confirm that the binding 
antibodies are specific to MT10109L and titered to assess the extent of antibodies present. In 
Stage 2, only samples testing positive in the antidrug antibody (ADA) confirmatory assay will be 
evaluated in the mouse protection assay (MPA). 
 
 
 
 
 
 
 
 
 
 
5.4. 
Other Safety Analyses 
5.4.1. 
Extent of Exposure 
Participants’ exposure to the study intervention will be summarized by duration of treatment 
exposure, number of treatment cycles, and treatment cycle interval duration. 
Duration of treatment exposure will be calculated for each extension treatment regimen
 
 based on the number of days between 
the date of the first injection of that treatment (F) and the date of study exit in the extension 
study (E). The actual calculation used will be E – F + 1. If the date of study exit is missing, the 
date of the last visit will be used. 
 
 
 
 
 
 
Participants’ exposure to study intervention will be summarized by total duration of treatment 
exposure 
 
 In addition, for the entire study, the number and percentage of 
participants receiving 1, 2, 3 up to 12 study interventions will be summarized. 


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5.4.1.1. 
Treatment Compliance 
Participants will receive all doses under the direct supervision of study site personnel. Study 
intervention compliance will not be calculated. 
The study site will keep an accurate drug disposition record that specifies the amount of study 
intervention administered to each participant and the date of administration. 
 
 


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5.4.2. 
Additional Safety Assessments 
No laboratory or electrocardiogram (ECG) data will be collected for this study. 
Urine pregnancy tests are performed prior to each treatment and at exit visit for females of 
childbearing potential. Participants with positive pregnancy test results will be listed by 
treatment regimen, including urine sample collection date, days since Day 1 treatment (of 
Studies MT10109L-001, -002, -005, or -006) and days since most recent treatment. 
 
 
 
 
 
  
5.5. 
Other Efficacy Analyses 
For US FDA, the efficacy analyses will be based on the ITT population. 
 
 
 
 
Continuous descriptive statistics include: N1 (number of participants with nonmissing values at 
both baseline and the specified postbaseline analysis visit), mean, SD, median, minimum, and 
maximum. 
Categorical variables will be summarized by number and percentage of participants. The 
proportions of participants who achieve the efficacy endpoints will be summarized with 
frequency tables. The 95% confidence interval for responders will be estimated based on the 
observed data by intervention group and by intervention cycle. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6. 
Supporting Documentation 
6.1. 
Appendix 1 List of Abbreviations 
 
AE 
adverse event 
BMI 
Body mass index 
BoNT/A 
botulinum toxin type A 
DB 
double blind 
ECG 
electrocardiogram, electrocardiographic 
EU 
European Union 
ELISA 
enzyme-linked immunosorbent assay 
US FDA 
United States food and drug administration 
 
 
 
 
 
 
GL 
glabellar lines 
HLT 
high level term 
ITT 
intent to treat 
LCL 
lateral canthal lines (also called crow’s feet lines/CFL) 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
MT10109L 
NivobotulinumtoxinA 
OL 
open-label 
 
 
PRO 
patient reported outcome 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis Software 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
WHO DDE 
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6.3. 
Appendix 3: Supporting Study Information 
6.3.1. 
Demographics 
The analysis and summary of all demographic and other baseline characteristics will be 
performed using the ITT 
 population unless otherwise specified. The lead-in and 
extension study possible treatment regimens will be used unless otherwise specified. 
Demographic data will be collected at the Studies MT10109L-001, - 002, -005, and -006 
screening visit, including age, gender, race, weight, height, and Body Mass Index (BMI). Age, 
weight, height, and BMI will be analyzed with the descriptive statistics (sample size, mean, SD, 
median, Min, and Max) by lead-in and extension study possible treatment regimens. Age group, 
gender, and race will be analyzed with frequency (counts and percentages) by lead-in and 
extension study possible treatment regimens. Age will be classified into 2 age groups: < 65 and 
≥ 65. Race will be classified as Caucasian and non-Caucasian. 
The algorithm for calculating age in years will be as follows: 
If the participant's birthday has been reached in the baseline (Day 1) year, age = year of 
baseline minus year of birth 
If the participant's birthday has not yet been reached in the baseline (Day 1) year, age = 
year of baseline minus year of birth -1 
 
6.3.2. 
Baseline and Disease Characteristics 
For the ITT population, the distribution of the baseline severity of GL and LCL at maximum 
contraction and at rest will be summarized for each area separately for the FWS assessments by 
lead-in and extension study possible treatment regimens. 
 
 
. 
6.3.3. 
Protocol Deviations 
Unique participants reporting significant protocol deviations will be summarized in total and by 
intervention group for the ITT population. 
A listing of any significant protocol deviations will be provided. 
6.3.4. 
Medical History 
Medical history includes all medical conditions that the participant had in the past or currently 
have prior to injection on the Day 1 visit of Studies MT10109L-001, -002, -005, and -006. The 
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tabulated by lead-in and extension study possible treatment regimens for the ITT population by 
MedDRA primary SOC in descending order. 
6.3.5. 
Prior/Concomitant/Follow-up Medications/Procedures 
Prior and concomitant medications/procedures will be tabulated by lead-in and extension study 
possible treatment regimens for the ITT population. 
6.3.5.1. 
Prior and Concomitant Medications 
Prior medications include all medications prior to the Day 1 Baseline Visit of Studies 
MT10109L-001, -002, -005, and -006, whether or not the medication is continuing beyond the 
Baseline Visit. Concomitant medications encompass all medicinal products that the participant 
was taking prior to the Studies MT10109L-001, -002, -005, and -006 Day 1 Baseline Visit that 
are ongoing at the visit, in addition to all medications that have a start date on or after the Day 1 
visit date. 
Handling of partial and missing date in CM for the determination of prior versus concomitant 
medication is described in section 6.4.6 
Concomitant medications will be summarized by treatment, WHO-DD Anatomical-Therapeutic-
Chemical (ATC) classification and PT, displaying counts and percentages of subjects who 
reported using at least one medication. All prior and concomitant medications will also be 
presented in a by-subject listing. 
 
 


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Prior and Concomitant ProceduresPrior procedure (with stop dates prior to first injection of 
MT10109L), and concomitant procedure (ongoing or medications with a start date after first 
injection of MT10109L). The frequency (number and percentages) of participants who have 
undergone each procedure will be tabulated for each lead-in and extension study possible 
treatment regimens by MedDRA SOC and PT.  
The tables will display counts and percentages of subjects who reported at least one procedure in 
each SOC and PT. At each level of summarization, a subject reporting more than one event will 
be counted only once using. All prior and concomitant procedure will be presented in a by-
subject listing, detailing the verbatim term, PT, SOC, start date and indication. 
 
 
 
 
 
6.4. 
Data Handling Convention 
6.4.1. 
Analysis Window 
For analyses by visit, the following visit windows will be used to determine visit assignment, 
based on the observed number of days relative to the start of each treatment cycle (the day of the 
injection) (Table 6-1). 


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If two or more values fall within the same analysis window, the one closest to the target date will 
be used. 
6.4.2. 
Repeated or Unscheduled Assessments of Safety Parameters 
If a participant has repeated assessments before the start of the first treatment, the results from 
the final non-missing assessment made prior to the start of the study intervention will be used as 
baseline. If end-of-study assessments are repeated or if unscheduled visits occur, the last non-
missing postbaseline assessment will be used as the end-of-study assessment for generating 
summary statistics. 


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6.4.3. 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE that started before the date of the first dose of study intervention, 
an intensity of mild will be assigned. If severity is missing for an AE that started on or after the 
date of the first dose of study intervention, an intensity of severe will be assigned. The imputed 
values for severity assessment will be used for the incidence summary; the values will be shown 
as missing in the data listings. 
6.4.4. 
Missing Causal Relationship to Study Intervention for Adverse Events 
If the causal relationship to the study intervention is missing for an AE that started on or after the 
date of the first dose of study intervention, a causality of yes will be assigned. The imputed 
values for causal relationship to study intervention will be used for the incidence summary; the 
values will be shown as missing in the data listings. 
6.4.5. 
Missing Date Information for Adverse Events 
Partial AE onset date will be imputed as follows: 1) if day is missing but month is not, impute 
the date as the first day of the month; 2) if both day and month are missing, impute the date as 
01 Jan; 3) if imputed onset date is before the first intervention, yet the corresponding AE was not 
observed pretreatment, then impute the onset date as the first treatment date. Imputed partial AE 
onset date will only be used to determine the AE onset cycle. 
Other partial AE dates will not be imputed. All partial dates will be listed “as is” in the data 
listings. If both AE onset date and first injection of MT10109L date’s time are recorded, 
datetime will be used for imputation in lead in study. 
 
6.4.6. 
Missing Date Information for Medications 
There will be no imputation for missing or partial start/end date for medication. Partial dates entered 
in the prior and CM form will be imputed for the purposes of determining whether the record is a 
concomitant or prior medication in analysis flag based on the following: 1) Medications that are not 
ongoing and have a medication stop date with a missing day and non-missing month will be assumed 
to occur on the last day of the non-missing month. 2) Medications that are not ongoing and have a 
medication stop date with missing day and month will be assumed to occur on the last day of the 
non-missing year (i.e., December 31).  
 
 


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7. 
References 
Beers MH. Anaerobic Bacteria. In: Beers MH, editor. The Merck Manual of Diagnosis and 
Therapy: Infectious Diseases. 18th ed. Whitehouse Station, NJ: Merck Research Laboratories; 
2006:1498-1499. 
Dmitrienko A, Molenberghs G, Chuang-Stein C, Offen W. Analysis of Clinical Trials Using 
SAS: A Practical Guide. SAS Institute, Cary, North Carolina 2005;104-10 
 
 


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