Clinical trial NCT02322333
Conditions: Migraine
Sponsor: Pharmalyte Solutions LLC
Start date: 2015-03-01; Completion date: 2017-06-01
Enrollment: 157 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind, placebo-controlled, randomized, multi-center study. Subjects agreeing to participate in the study and meet the entry criteria assessed at the screening visit, will begin a 28 day baseline period to confirm their diagnosis, as well as establish baseline migraine characteristics. During this baseline period, subjects will continue treating their migraines as usual, simply recording the information in a daily headache diary. Subjects who, after completing the baseline, continue to meet entrance criteria will be eligible to enter into the treatment phase and be randomized according to the Clinvest generated randomization schedule. Approximately 142 subjects (71 subjects per arm) will be randomized and enter the treatment phase receiving MLD10 or placebo in a 1:1 design at 6 United States sites. Diary assessments will collect study medication adherence, pain severity, headache symptoms, acute medication usage, and unusual symptoms. Serum samples will be collected and analyzed for ionized magnesium, electrolytes, and creatinine.

Detailed description:
This is a multi-center, double-blind, randomized, placebo-controlled, parallel study of MLD10 for the prevention of migraine headache. The study population will consist of approximately 142 male and female subjects between 18 and 65 years of age with frequent episodic migraine as defined by International Classification of Headache Disorders-3beta criteria. Two MLD10 (243 mg (milligrams) of elemental magnesium) or placebo caplets will be taken twice daily for a total daily dose of 486 mg.

VISIT 1 - SCREENING

The following will be completed at Visit 1:

1. Obtain written Informed Consent. The informed consent will be obtained in accordance with Good Clinical Practices (GCP) and all applicable regulatory requirements from each subject prior to participation in the study.
2. Verify Inclusion/Exclusion Criteria. Subjects will meet all the inclusion and none of the exclusion criteria.
3. Obtain demographics (race, ethnicity, sex, date of birth)
4. Obtain medical, medication, and headache history. Data collected will include medical history and diagnoses, age at onset of migraine and other pertinent migraine/headache history, history of acute and prophylactic headache medications within the past 30 days, and history of other recent/concomitant medications.
5. Obtain date of last menstrual cycle and perform urine pregnancy test, if appropriate. Results of the pregnancy test must be negative to continue in study.
6. Perform physical and neurological examinations.
7. Measure vital signs (height, weight, resting heart rate, and blood pressure).
8. Review Baseline Headache Diary. Subjects will be instructed to complete a daily online headache diary. Assessments to be captured are start/stop time, severity, associated symptoms, use of rescue medications, and unusual symptoms.
9. Administer Columbia-Suicide Severity Rating Scale (C-SSRS).
10. Schedule Visit 2.

VISIT 2 - RANDOMIZATION

1. Verify Inclusion/Exclusion Criteria. Subjects must continue to meet all inclusion (including ≥ 3 days of migraine during baseline) and none of the exclusion criteria.
2. Perform urine pregnancy test, if appropriate. Results of the pregnancy test must be negative to continue in study.
3. Measure vital signs (weight, resting heart rate, and blood pressure).
4. Record any changes to concomitant medications.
5. Record any Serious Adverse Events (SAE) since signing the Informed Consent.
6. Review Baseline Headache Diary for completeness and continuing eligibility.
7. Randomize subject
8. Review Month 1 Headache Diary instructions (same instructions as those discussed for Baseline Headache Diary).
9. Dispense Month 1 study medication. Subjects will be instructed how to take study medication, prohibited medications/foods, dosage limitations of study medication, and storage requirements. Subjects will be instructed to return all used/partially used/unused study medication at next office visit and medications reconciliation will be performed to ensure a compliance of at least 80%. Subjects not complying at an 80% level will be withdrawn, unless otherwise approved by the Sponsor and/or Clinvest. (Estimated to be \< 10%)
10. Administer C-SSRS.
11. Administer MIDAS.
12. Collect serum samples for electrolytes, creatinine, and ionized Mg.
13. Schedule Visit 3.

VISIT 3 - END OF TREATMENT PERIOD MONTH 1

1. Record any changes to concomitant medications.
2. Record any Non-Serious Adverse Events (NSAE) and/or SAEs.
3. Perform urine pregnancy test, if appropriate. Results of the pregnancy test must be negative to continue in study.
4. Measure vital signs (weight, resting heart rate, and blood pressure).
5. Review Month 1 Headache Diary for completeness.
6. Review instructions for Month 2 Headache Diary (same instructions as those discussed for Month 1 Headache Diary).
7. Collect Month 1 unused study medication and used packaging. Confirm 85% compliance of medication usage per study protocol.
8. Dispense Month 2 study medication and review the dosage limitations of study medication, storage requirements, and to return all used/partially used/unused study medication at next office visit.
9. Perform drug accountability.
10. Administer C-SSRS.
11. Collect serum samples for electrolytes, creatinine, and ionized Mg.
12. Schedule Visit 4.

VISIT 4 - END OF TREATMENT PERIOD MONTH 2

1. Record any changes to concomitant medications.
2. Record any NSAEs/SAEs.
3. Perform urine pregnancy test, if appropriate. Results of the pregnancy test must be negative to continue in study.
4. Measure vital signs (weight, resting heart rate, and blood pressure).
5. Review Month 2 Headache Diary for completeness.
6. Review instructions for Month 3 Headache Diary (same instructions as those discussed for Month 2 Headache Diary).
7. Collect Month 2 unused study medication and used packaging. Confirm 85% compliance for medication usage per study protocol.
8. Dispense Month 3 study medication and review the dosage limitations of study medication, storage requirements, and to return all used/partially used/unused study medication at next office visit.
9. Perform drug accountability.
10. Administer C-SSRS.
11. Collect serum samples for electrolytes, creatinine, and ionized Mg.
12. Schedule Visit 5.

VISIT 5 - END OF TREATMENT PERIOD MONTH 3

1. Record any changes to concomitant medications.
2. Record any NSAEs/SAEs.
3. Perform urine pregnancy test, if appropriate.
4. Measure vital signs (weight, resting heart rate, and blood pressure)
5. Perform physical/neurological examinations.
6. Collect Month 4 unused study medication and used packaging.
7. Perform drug accountability.
8. Administer SGIC \& complete PGIC.
9. Administer MIDAS.
10. Administer C-SSRS.
11. Collect serum samples for electrolytes, creatinine, and ionized Mg.
12. Exit subject.

Arms: arm 1: Subjects randomized to MLD10 will be dispensed a 28 day supply of magnesium L-lactate dehydrate for daily treatment. A total of 120 caplets will be given each time at Visit 2, 3, and 4. Additional overage will be given to account for the 3 day window. Subjects will be instructed to take two caplets of study medication BID (twice a day) at about the same time each day. Subjects will be instructed regarding storage requirements and will be asked to return all used/partially used/unused medication containers at the next office visit. arm 2: Subjects randomized to placebo will be dispensed a 28 day supply of matching placebo for daily treatment. A total of 120 caplets will be given each time at Visit 2, 3, and 4. Additional overage will be given to account for the 3 day window. Subjects will be instructed to take two caplets of study medication BID (twice a day) at about the same time each day. Subjects will be instructed regarding storage requirements and will be asked to return all used/partially used/unused medication containers at the next office visit.
Interventions: intervention 1: MLD10 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
1/2/15, Revised 4/20/16 
1 
 
 STUDY TITLE: A Multicenter, Randomized, Double-blind, Placebo-controlled Study 
Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
 
PROTOCOL NO: 
MLD10-002 
 
SPONSOR:  
 
Pharmalyte Solutions LLC 
  
 
 
 
580 Commerce Street  
Suite 100 
Southlake, TX 76092 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


1/2/15, Revised 4/20/16 
2 
 
 
A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the 
Efficacy and Safety of MLD10 in the Prevention of Migraine Headache in Adults  
 
INVESTIGATOR SIGNATURE PAGE 
 
I agree to: 
 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Clinvest in confidence and, when this information is 
submitted to an Institutional Review Board (IRB), it will be submitted with a designation 
that the materials are confidential. 
I have read and agree to follow this protocol. 
 
 
______________________________ 
____________________________ ____________ 
Investigator Printed Name 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 


1/2/15, Revised 4/20/16 
3 
 
TABLE OF CONTENTS 
 
INDICATION ..................................................................................................................................6 
 
STUDY PURPOSE ..........................................................................................................................6 
 
SUMMARY OF STUDY DESIGN .................................................................................................6 
 
POPULATION SAMPLE ................................................................................................................6 
 
STUDY MEDICATION ..................................................................................................................7 
 
BACKGROUND & STUDY RATIONALE ...................................................................................7 
 
PRIMARY OBJECTIVE .................................................................................................................7 
 
SECONDARY OBJECTIVES.........................................................................................................7 
 
EXPLORATORY OBJECTIVES ....................................................................................................7 
 
SAFETY OBJECTIVES ..................................................................................................................7 
 
SUBJECT SELECTION ..................................................................................................................8 
 
 
POWER ANALYSIS .......................................................................................................................8 
 
INCLUSION CRITERIA.................................................................................................................8 
 
EXCLUSION CRITERIA ...............................................................................................................9 
 
STUDY DESIGN.............................................................................................................................9 
 
INFORMED CONSENT .................................................................................................................9 
 
VISIT 1 - SCREENING.................................................................................................................10 
 
VISIT 2 - RANDOMIZATION .....................................................................................................10 
 
VISIT 3 - END OF TREATMENT PERIOD MONTH 1 .............................................................11 
 
VISIT 4 - END OF TREATMENT PERIOD MONTH 2 .............................................................11 
 
VISIT 5 - END OF TREATMENT PERIOD MONTH 3 .............................................................12 
 
TABLE 1. - STUDY PROCEDURES ...........................................................................................12 


1/2/15, Revised 4/20/16 
4 
 
TABLE OF CONTENTS CONTINUED 
STUDY MEDICATION RANDOMIZATION .............................................................................12 
 
Group A .................................................................................................................13 
                       Group B ..................................................................................................................13 
RESCUE MEDICATIONS ............................................................................................................13 
CONCOMITANT MEDICATIONS .............................................................................................13 
 
Allowed Medications .............................................................................................13 
                        Prohibited Medications ..........................................................................................13 
HEADACHE DIARY ....................................................................................................................14 
UNSCHEDULED VISITS.............................................................................................................14 
BLINDING/UNBLINDING ..........................................................................................................14 
DISCONTINUATION/WITHDRAWAL FROM STUDY ...........................................................15 
REPORTING PREGNANCY ........................................................................................................15 
REPORTING ADVERSE EVENTS .............................................................................................15 
 
Non-Serious Adverse Event (NSAE).....................................................................16 
 
Serious Adverse Event (SAE)   ..............................................................................16 
CLINICAL SUPPLIES ..................................................................................................................17 
STORAGE REQUIREMENTS .....................................................................................................17 
CONFIDENTIALITY....................................................................................................................17 
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT .....................................................18 
QUALITY CONTROL/ASSURANCE .........................................................................................18 
STUDY DOCUMENTATION  .....................................................................................................19 
RECORD RETENTION ................................................................................................................19 


1/2/15, Revised 4/20/16 
5 
 
TABLE OF CONTENTS CONTINUED 
INSTITUTIONAL REVIEW BOARD..........................................................................................20 
TRAINING ....................................................................................................................................20 
SAFETY MEASURES ..................................................................................................................21 
 
Adverse Events ......................................................................................................21 
 
Physical Examination.............................................................................................21 
 
Clinical Laboratory Tests .......................................................................................21 
 
Vital Signs ..............................................................................................................21 
 
Columbia Suicide Severity Rating Scale (C-SSRS) ..............................................21 
SUMMARY OF METHODS OF DATA COLLECTION ............................................................22 
STATISTICAL ANALYSIS .........................................................................................................23 
 
Modified Intent-to-Treat Population ......................................................................23 
 
Safety Population ...................................................................................................23 
PRIMARY ENDPOINT ................................................................................................................23 
SECONDARY ENDPOINTS ........................................................................................................24 
EXPLORATORY ENDPOINTS ...................................................................................................24 
SAFETY ENDPOINTS .................................................................................................................24 
COLLECTION AND DERIVATION OF ENDPOINTS ..............................................................24 
 
Primary Efficacy Variable .....................................................................................24 
 
Secondary Efficacy Variables ................................................................................25 
APPENDIX I .................................................................................................................................26 
APPENDIX II ................................................................................................................................27 
 


1/2/15, Revised 4/20/16 
6 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY EVALUATING THE EFFICACY AND SAFETY OF MLD10 IN THE 
PREVENTION OF MIGRAINE HEADACHE IN ADULTS 
 
INDICATION 
For the prophylaxis of migraine headaches in adults 
 
STUDY PURPOSE 
• 
To evaluate the daily use of MLD10 and placebo for the treatment of migraine, as 
measured by the change from baseline in the number of migraine headache days of 
subjects treated for 3 months. 
• 
To compare daily use of MLD10 and placebo as measured by: 
- change in the quantitative and qualitative aspects of migraine headaches from 
baseline, during treatment, and at the conclusion of a 3-month treatment period. 
- safety and tolerability measures in migraine headache subjects through the 
monitoring of adverse events (AEs) and clinical chemistry values. 
 
SUMMARY OF STUDY DESIGN 
This is a double-blind, placebo-controlled, randomized, multi-center study.  Subjects agreeing to 
participate in the study and meet the entry criteria assessed at the screening visit, will begin a 28 
day baseline period to confirm their diagnosis, as well as establish baseline migraine 
characteristics.  During this baseline period, subjects will continue treating their migraines as 
usual, simply recording the information in a daily headache diary.  Subjects who, after 
completing the baseline, continue to meet entrance criteria will be eligible to enter into the 
treatment phase and be randomized according to the Clinvest generated randomization schedule.  
Approximately 142 subjects (71 subjects per arm) will be randomized and enter the treatment 
phase receiving MLD10 or placebo in a 1:1 design at a maximum of 8 US sites.  Diary 
assessments will collect study medication adherence, pain severity, headache symptoms, acute 
medication usage, and unusual symptoms. Serum samples will be collected and analyzed for 
ionized Mg, electrolytes, and creatinine.  
 
The study consists of 5 visits: 
Baseline Period: 
Visit 1 (Screening/Baseline Period) 
Treatment Period: 
Visit 2 (Randomization/Treatment Period Month 1) 
 
Visit 3 (Treatment Period Month 2) 
 
Visit 4 (Treatment Period Month 3) 
 
Visit 5 (Final Visit) 
 
POPULATION SAMPLE 
Subjects in the study are those: 
• 
who have at least a 3 month history of 3-14 migraines, with or without aura, as 
defined by International Classification of Headache Disorders (ICHD) -3 beta 
(Appendix 1) or treat with a ergot or triptan and received relief. 
• 
who received a diagnosis of migraine before age 50. 
• 
who have used acute headache medication 14 or fewer days per month in the previous 
3 months. 


1/2/15, Revised 4/20/16 
7 
 
STUDY MEDICATION 
Subjects will receive Investigational Drug Product MLD10 as follows: 2 MLD10 caplets, oral, 
twice daily or placebo caplets as follows: 2 placebo caplets, oral, twice daily. 
 
BACKGROUND & STUDY RATIONALE 
Magnesium is frequently used in the treatment and prevention of migraine, though there are 
relatively few clinical trials supporting its efficacy.  While there is a sound scientific rationale for 
magnesium as a migraine preventative, different forms of magnesium differ significantly in their 
solubility and bioavailability.  In addition, there are challenges in measuring bioactive 
magnesium levels in the body.  Consequently, a discussion of the efficacy of magnesium needs 
to be specific to the formulation of magnesium being studied, its ability to be adequately 
absorbed, and physiologically active. 
 
Magnesium is recognized to block the N-methyl-D-aspartate ion-dependent channel.  Low levels 
of magnesium increase the sensitivity of the NMDA receptor to glutamate.  Glutamate is an 
excitatory neurotransmitter and is considered central to the development of cortical spreading 
depression.  In addition, glutamate is considered to play an excitatory role in the hyper-vigilant 
migraine nervous system.  Thus, magnesium properly utilized physiologically has significant 
potential to protect the nervous system from migraine. 
 
PRIMARY OBJECTIVE  
To compare the change from baseline to treatment period months 1, 2, and 3 in the 
number of migraine headache days of subjects treated with MLD10 versus placebo.  
 
SECONDARY OBJECTIVES 
To compare change from baseline of subjects treated with MLD10 versus placebo on the 
following parameters during a 3 month treatment period: 
• the number of headache days 
• the average headache duration 
• pain severity at headache onset 
• the use of acute medications 
• Migraine Disability Assessment Scale (MIDAS) scores 
• Subject Global Impression of Change (SGIC) 
• Physician Global Impression of Change (PGIC) 
 
EXPLORATORY OBJECTIVES 
To compare the change from baseline of subjects treating with MLD10 versus placebo on 
the following parameters during a 3 month treatment period. 
• migraine with aura days 
• serum ionized magnesium  
 
SAFETY OBJECTIVES 
Safety assessments will include monitoring the parameters during the length of the study. 
• 
adverse events 
• 
physical examination 
• 
urine pregnancy tests for all females of childbearing potential 


1/2/15, Revised 4/20/16 
8 
 
• 
vital signs including blood pressure, pulse rate, and weight 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
concomitant medications 
• 
clinical chemistry measurements 
 
SUBJECT SELECTION 
Approximately 142 subjects will be randomized from the clinic and general population with a 
history of mild to severe migraine, with or without aura, that meets the International 
Classification of Headache Disorders (ICHD-3 beta) definition for episodic migraine with a 
frequency of 3-14 days of migraine (or headache treated with migraine specific medication) per 
month.  Subjects will have a stable history of headaches meeting the above parameters for at 
least 3 months prior to enrollment.  Subjects on migraine preventative medications will be 
required to be on a stable regimen for 30 days prior to and throughout the study period.  
 
POWER ANALYSIS 
A power analysis, using GPower Version 3.1.7, indicated a total sample size of 128 subjects 
would be needed to detect medium effects (d = .25) with 80% power using an analysis of 
covariance (ANCOVA) test to include fixed effects, main effects, and interactions with alpha 
being .05.  Given an estimated 10% early termination rate, a total estimated sample size of 142 
subjects is needed.   
 
INCLUSION CRITERIA 
Subjects must meet the following inclusion criteria: 
1. male or female, in otherwise good health, 18 to 65 years of age.   
2. history of frequent episodic migraine (3-14 migraine days per month) (with or 
without aura) according to the ICHD-3 beta for at least 3 months.  
3. onset of migraine before age 50.  
4. stable history of migraine at least 3 months prior to screening. 
5. not currently taking a migraine preventive or has been taking preventive for at least 
30 days prior to screening and agrees to not start, stop, or change medication and/or 
dosage during the study period. 
6. if female of childbearing potential, has a negative urine pregnancy test at Visits 1-5 
and uses, or agrees to use, for the duration of the study, a medically acceptable form 
of contraception as listed:  
• 
complete abstinence from intercourse from 2 weeks prior to administration of 
study drug, throughout the study, and for 7 days after completion or 
premature discontinuation from the study; surgically sterile (hysterectomy or 
tubal ligation or otherwise incapable of pregnancy); sterilization of male 
partner when in a monogamous relationship; intrauterine device with 
published data showing lowest expected failure rate is less than 1% per year; 
double barrier method (i.e., 2 physical barriers OR 1 physical barrier plus 
spermicide) for a least 1 month prior to Visit 1 and throughout study; or 
hormonal contraceptives for at least 3 months prior to Visit 1 and throughout 
study. 
7. completion of online diary must be ≥ 80% compliance, unless otherwise approved by 
the Sponsor and/or Clinvest.   


1/2/15, Revised 4/20/16 
9 
 
EXCLUSION CRITERIA 
Subjects must NOT meet any of the following exclusion criteria: 
1. unable to understand the study requirements, the informed consent, or complete 
headache records as required per protocol. 
2. pregnant, actively trying to become pregnant, or breast-feeding. 
3. diagnosed with ICHD-3 beta criteria for Chronic Migraine within 3 months prior to 
screening, at the time of screening, and/or during the baseline period. 
4. experienced the following migraine variants: basilar migraine, aura without headache, 
familial hemiplegic migraine, complicated migraine, ophthalmoplegic migraine and 
retinal migraine within the last year. 
5. history of medication overuse headache (MOH) (Appendix II) in the 3 months prior 
to study enrollment or during the baseline phase.  
6. history of medication overuse (MO) of ergotamines, triptans, opioids, analgesics, 
NSAIDS and combination therapies, as defined by ICHD-3 beta criteria and/or MO 
during baseline period. 
7. history of substance abuse and/or dependence, in the opinion of the Investigator. 
8. history of impaired renal function that, in the investigator’s opinion, contraindicates 
participation in this study. 
9. unstable neurological condition or a significantly abnormal neurological examination 
with focal signs or signs of increased intracranial pressure. 
10. suffers from a serious illness, or an unstable medical condition, one that could require 
hospitalization, or could increase the risk of adverse events. 
11. has significant risk of suicide, defined as a “yes” answer to any of the following 
questions on the Columbia-Suicide Severity Rating Scale (C-SSRS), either at the 
screening visit (when assessing the prior 12 months) or at visit 2 (when assessing time 
since the screening visit): 
a. Questions 4 or 5 on the suicidal ideation section 
b. Any question on any item in the suicidal behavior section 
12. any psychiatric disorder with psychotic features, and/or any other psychiatric disorder 
not stable or well controlled, that would interfere in their ability to complete study 
activities.  
13. hypersensitivity, intolerance, or contraindication to the use of magnesium L-lactate 
dehydrate or any of its components. 
14. received any investigational agents within 30 days prior to Visit 1. 
15. plans to participate in another clinical study at any time during this study. 
 
STUDY DESIGN 
This is a multi-center, double-blind, randomized, placebo-controlled, parallel study of MLD10 
for the prevention of migraine headache.  The study population will consist of approximately 142 
male and female subjects between 18 and 65 years of age with frequent episodic migraine as 
defined by ICHD-3 beta criteria.  Two MLD10 (243 mg of elemental magnesium) or placebo 
caplets will be taken twice daily for a total daily dose of 486 mg.   
 
INFORMED CONSENT 
The investigator must obtain documented consent from each potential subject, or legally 
authorized representative, prior to any study related procedures being performed.  Consent must 


1/2/15, Revised 4/20/16 
10 
 
be documented by the subject’s dated signature on an Informed Consent Form (ICF) along with 
the dated signature of the persons conducting the consenting process.  A copy of the signed and 
dated consent form should be given to the subject before participating in the study.   
 
If the subject is illiterate, an impartial witness should be present during the entire informed 
consent reading and discussion.  Afterward, the subject should sign and date the informed 
consent, if capable.  The impartial witness should also sign and date the informed consent along 
with the person conducting the consent process.   
 
VISIT 1 - SCREENING 
The following will be completed at Visit 1: 
1. Obtain written Informed Consent.  The informed consent will be obtained in 
accordance with Good Clinical Practices (GCP) and all applicable regulatory 
requirements from each subject prior to participation in the study.   
2. Verify Inclusion/Exclusion Criteria.  Subjects will meet all the inclusion and none of 
the exclusion criteria. 
3. Obtain demographics (race, ethnicity, sex, date of birth) 
4. Obtain medical, medication, and headache history.  Data collected will include 
medical history and diagnoses, age at onset of migraine and other pertinent 
migraine/headache history, history of acute and prophylactic headache medications 
within the past 30 days, and history of other recent/concomitant medications. 
5. Obtain date of last menstrual cycle and perform urine pregnancy test, if appropriate.  
Results of the pregnancy test must be negative to continue in study.  
6. Perform physical and neurological examinations. 
7. Measure vital signs (height, weight, resting heart rate, and blood pressure). 
 
8. Review Baseline Headache Diary.  Subjects will be instructed to complete a daily 
online headache diary.  Assessments to be captured are start/stop time, severity, 
associated symptoms, use of rescue medications, and unusual symptoms.   
9. Administer Columbia-Suicide Severity Rating Scale (C-SSRS). 
10. Schedule Visit 2. 
 
 VISIT 2 - RANDOMIZATION 
1. Verify Inclusion/Exclusion Criteria.  Subjects must continue to meet all inclusion 
(including ≥ 3 days of migraine during baseline) and none of the exclusion criteria.  
2. Perform urine pregnancy test, if appropriate.  Results of the pregnancy test must be 
negative to continue in study.  
3. Measure vital signs (weight, resting heart rate, and blood pressure). 
4.  Record any changes to concomitant medications. 
5.  Record any Serious Adverse Events (SAE) since signing the Informed Consent. 
6.  Review Baseline Headache Diary for completeness and continuing eligibility.   
7.  Randomize subject  
8. Review Month 1 Headache Diary instructions (same instructions as those discussed 
for Baseline Headache Diary). 
 9. Dispense Month 1 study medication.  Subjects will be instructed how to take study 
medication, prohibited medications, dosage limitations of study medication, and 
storage requirements. Subjects will be instructed to return all used/partially 


1/2/15, Revised 4/20/16 
11 
 
used/unused study medication at next office visit and medications reconciliation will 
be performed to ensure a compliance of at least 80%.  Subjects not complying at an 
80% level will be withdrawn, unless otherwise approved by the Sponsor and/or 
Clinvest. (Estimated to be < 10%) 
10. Administer C-SSRS. 
11. Administer MIDAS. 
12. Collect serum samples for electrolytes, creatinine, and ionized Mg. 
13. Schedule Visit 3. 
 
 VISIT 3 - END OF TREATMENT PERIOD MONTH 1 
1.  Record any changes to concomitant medications. 
2. Record any Non-Serious Adverse Events (NSAE) and/or SAEs. 
3. Perform urine pregnancy test, if appropriate.  Results of the pregnancy test must be 
negative to continue in study.  
4. Measure vital signs (weight, resting heart rate, and blood pressure). 
5. Review Month 1 Headache Diary for completeness. 
6. Review instructions for Month 2 Headache Diary (same instructions as those 
discussed for Month 1 Headache Diary). 
7. Collect Month 1 unused study medication and used packaging.  Confirm 85% 
compliance of medication usage per study protocol.  
8. Dispense Month 2 study medication and review the dosage limitations of study 
medication, storage requirements, and to return all used/partially used/unused study 
medication at next office visit. 
 9. Perform drug accountability. 
10. Administer C-SSRS. 
11. Collect serum samples for electrolytes, creatinine, and ionized Mg. 
12. Schedule Visit 4. 
 
VISIT 4 - END OF TREATMENT PERIOD MONTH 2 
1. Record any changes to concomitant medications. 
2. Record any NSAEs/SAEs. 
3. Perform urine pregnancy test, if appropriate.  Results of the pregnancy test must be 
negative to continue in study.  
4. Measure vital signs (weight, resting heart rate, and blood pressure). 
5. Review Month 2 Headache Diary for completeness.   
6. Review instructions for Month 3 Headache Diary (same instructions as those 
discussed for Month 2 Headache Diary). 
7. Collect Month 2 unused study medication and used packaging.  Confirm 85% 
compliance for medication usage per study protocol.  
8. Dispense Month 3 study medication and review the dosage limitations of study 
medication, storage requirements, and to return all used/partially used/unused study 
medication at next office visit.  
9. Perform drug accountability. 
 
10. Administer C-SSRS. 
11. Collect serum samples for electrolytes, creatinine, and ionized Mg. 
12. Schedule Visit 5. 


1/2/15, Revised 4/20/16 
12 
 
 VISIT 5 - END OF TREATMENT PERIOD MONTH 3 
1. Record any changes to concomitant medications. 
2. Record any NSAEs/SAEs. 
3. Perform urine pregnancy test, if appropriate.   
4. Measure vital signs (weight, resting heart rate, and blood pressure) 
5. Perform physical/neurological examinations.     
6. Collect Month 4 unused study medication and used packaging.    
7. Perform drug accountability.  
8. Administer SGIC & complete PGIC. 
9. Administer MIDAS. 
10. Administer C-SSRS. 
  
11. Collect serum samples for electrolytes, creatinine, and ionized Mg. 
12. Exit subject. 
 
Table 1. Study Procedures 
 
Screening 
Randomization 
Treatment 
Visit 1 
Day 0 
 
Visit 2 
Day 29 
(+/- 3) 
Visit 3 
Day 58 
(+/- 3) 
Visit 4 
Day 87 
(+/- 3) 
Visit 5 
Day 116 
(+/- 3) 
Informed Consent 
X 
 
 
 
 
Physical/Neurological Exam 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
Verify Inclusion/Exclusion 
X 
X 
 
 
 
Subject Randomization 
 
X 
 
 
 
Medical History 
X 
 
 
 
 
Migraine History 
X 
 
 
 
 
Medication History 
X 
 
 
 
 
Update Medications 
 
X 
X 
X 
X 
Urine Pregnancy Test  
X 
X 
X 
X 
X 
SGIC 
 
 
 
 
X 
PGIC 
 
 
 
 
X 
Dispense Study Medication 
 
X 
X 
X 
 
Drug Accountability 
 
 
X 
X 
X 
Headache Diary 
X 
X 
X 
X 
 
Review Diary 
 
X 
X 
X 
X 
Collect Adverse Events 
 
X 
X 
X 
X 
Administer C-SSRS 
X 
X 
X 
X 
X 
Administer MIDAS 
 
X 
 
 
X 
Serum Electrolytes & 
Creatinine  
 
X 
X 
X 
X 
Serum Ionized Mg 
 
X 
X 
X 
X 
 
STUDY MEDICATION RANDOMIZATION 
Eligible subjects will be randomized 1:1 to receive magnesium L-lactate dehydrate (243 mg of 
elemental mg++ BID for a total of 486mg daily) or placebo at Visit 2.  If at any time during the 


1/2/15, Revised 4/20/16 
13 
 
study the subject withdrawals from the study, they will be instructed to return all used packaging 
and unused medication.   
Group A 
Subjects randomized to MLD10 (Group A) will be dispensed a 28 day supply of 
magnesium L-lactate dehydrate 10 mEq (121.5 mg of elemental mg++ caplets) for 
daily treatment.  A total of 120 caplets will be given each time at Visit 2, 3, and 4.  
Additional overage will be given to account for the 3 day window.  Subjects will be 
instructed to take two caplets of study medication BID at about the same time each day 
(i.e. 8AM & 8PM for a total of 486mg’s of elemental mg++ per day).  Subjects will be 
instructed regarding storage requirements and will be asked to return all used/partially 
used/unused medication containers at the next office visit.  
 
Group B 
Subjects randomized to placebo (Group B) will be dispensed a 28 day supply of 
matching placebo for daily treatment.  A total of 120 caplets will be given each time at 
Visit 2, 3, and 4.  Additional overage will be given to account for the 3 day window.  
Subjects will be instructed to take two caplets of study medication BID at about the 
same time each day (i.e. 8AM & 8PM).  Subjects will be instructed regarding storage 
requirements and will be asked to return all used/partially used/unused medication 
containers at the next office visit.  
 
RESCUE MEDICATION 
Subjects will be instructed they may take their investigator approved rescue medications for 
headaches, if needed.  Rescue medication usage and dosage will be recorded on the headache 
diary. 
 
CONCOMITANT MEDICATIONS 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
investigator. Concomitant medication usage and dosage will be recorded on the concomitant 
medication form. 
 
Routine medications, including migraine preventative medications, should be maintained on a 
stable dose and regimen for the duration of the study period.  Additionally, any concomitant 
chronic therapies should be maintained at a stable dose and dose regimen during the study. 
 
 Allowed Medications 
1. All acute migraine medications currently taken by subject at Visit 1 will be 
allowed during the study. 
2. All migraine preventative medications, excluding magnesium, that are currently 
taken by subject at Visit 1 will be allowed if on a stable dose for at least 30 days 
prior to Visit 1 and subject agrees to continue at that dose throughout the study.   
 
Prohibited Medications 
Any medication containing magnesium 30 days prior to screening. 
 
 


1/2/15, Revised 4/20/16 
14 
 
HEADACHE DIARY 
The primary and much of the secondary endpoints will be derived from the electronic daily 
headache diary.  Site personnel will be responsible for instructing subjects on the requirement for 
timely and daily completion of the electronic diary.  Each day, the subject will be asked to record 
diary data for the previous day (24 hour period).  If a subject does not experience a headache in 
the previous 24 hour period, the diary must still be completed and recorded as no headache.  
Subject’s diaries may vary day to day based on their responses.  Subjects will be asked to 
document all headaches experienced regardless of severity for one month.  All subjects should 
have at least 80% compliance with diary completion throughout the length of the study.  Subjects 
will record headache severity, symptoms, use of acute medications, as well as additional 
questions as required.  Headache severity will be subjectively rated by the subject as follows: no 
pain, mild pain, moderate pain, or severe pain.  These ratings will be collected at pre-defined 
time points.       
 
UNSCHEDULED VISITS 
If a subject has an unscheduled visit, the unscheduled visit form must be completed.  If the visit 
occurs for safety reasons, all relevant safety data should be captured and reported on the 
appropriate forms.  If the unscheduled visit results in an early termination, all applicable final 
study visit procedures will be performed and the early termination form will need to be 
completed as well. 
 
BLINDING/UNBLINDING 
At randomization (Visit 2), neither the subject nor the investigator will be aware to which 
treatment group the subject has been assigned.  If needed, for safety and proper treatment of the 
subject, the investigator can unblind the subject’s treatment assignment to determine which 
treatment has been assigned and institute appropriate follow-up care.  When possible, Clinvest 
should be notified prior to unblinding study medication.    
 
Individual unblinding envelopes are shipped with study medication.  Each study medication kit 
has a corresponding unblinding envelope.  Unblinding will include matching the kit and 
unblinding envelope with the subject drug number. 
 
To unblind a subject without breaking the blind for remaining subjects’ treatment the following 
instructions described below will be followed: 
 
• 
Obtain the security envelope containing the unblinding envelopes. 
• 
Remove the unblinding envelope with the study drug number corresponding with the 
study medication kit dispensed to the subject. 
• 
Break the seal of the unblinding envelope and remove the subjects’ treatment label. 
• 
Return the subjects’ treatment label to the unblinding envelope. 
• 
Return the unblinding envelope to the security envelope. 
• 
Document on the unblinding form located in the eAdmin Binder.  
• 
Email copy of unblinding form to study@clinvest.com within 24 hours of unblinding. 
• 
Complete and email or fax the Sterling IRB, unanticipated problem report form, to 
Sterling IRB within 10 business days of unblinding.  
 


1/2/15, Revised 4/20/16 
15 
 
DISCONTINUATION/WITHDRAWAL FROM STUDY 
All subjects who withdraw from the study, for any reason, must return all study medication and 
supplies to the investigator or his/her delegate at the first available opportunity.   
Subjects may withdraw at any time or be dropped from the study at the discretion of the 
investigator or Clinvest if he/she violates the study plan or for administrative and/or safety 
reasons.  When a subject discontinues/withdraws prior to study completion, all applicable 
activities scheduled for the final study visit should be performed at the time of discontinuation, 
as well as the completion of the early termination form and unscheduled visit form (if 
appropriate).  Any adverse experiences which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in the adverse event reporting section of this protocol.   
 
REPORTING PREGNANCY 
Although not considered an adverse event, if a female of childbearing potential becomes 
pregnant during the study, the investigator will notify Clinvest and Pharmalyte Solutions LLC by 
phone immediately after the pregnancy is confirmed.  The subject will not receive any further 
treatment and will be withdrawn from the study.  The subject should be followed for 12 weeks 
after the last study treatment and at least 6-8 weeks following the report of pregnancy, before 
being exited from the study.  The investigator will (1) notify the subject’s physician that the 
subject was being treated with an investigational drug MLD10 and (2) follow the progress of the 
pregnancy until delivery.  The investigator should document the outcome of the pregnancy and 
provide a copy of the documentation to Clinvest. 
 
REPORTING ADVERSE EVENTS 
The investigator will be responsible for the detection, collection, and evaluation of all events 
meeting the definition of an adverse event (AE).  An adverse event is defined as any untoward 
medical occurrence in a subject or clinical investigation subject administered a medicinal product 
and which does not necessarily have a causal relationship with the study product.  An adverse 
event can therefore be any unfavorable and unintended sign (including abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the study product, whether 
or not related to the study product.   
 
An adverse event observed after the initial dose of the study product will be considered a 
“treatment-emergent adverse event”.  Treatment-emergent adverse events will be analyzed and 
discussed in the clinical study report for this study.  Adverse event terms should include a 
diagnosis, as available, in preference to the listing of individual signs and symptoms.  If a 
diagnosis is not possible, each sign and symptom should be recorded as an individual adverse 
event.   
 
All adverse events, whether or not related to the study drug, must be completely documented on 
the appropriate adverse event eCRF (electronic case report form) page.  If a subject is withdrawn 
from the study due to an adverse event, this must also be recorded on the appropriate eCRF 
pages.   
 
The site staff must record all directly observed AEs and all spontaneously reported AEs.  At each 
visit, the site staff will ask the subject a non-specific question (e.g., “Have you noticed any 


1/2/15, Revised 4/20/16 
16 
 
change in your health since your last visit?”) to assess AE occurrence since the last report or 
visit.   
 
Non-Serious Adverse Event (NSAE) 
NSAE’s will be collected beginning after the first dose of study medication or within 14 
days following cessation of treatment and will include any change from the subject’s 
condition at Visit 2.  These include physical findings, clinical signs and symptoms, or 
sequelae.  Any worsening (i.e. any clinically significant adverse change in the frequency 
and/or intensity) of a preexisting condition which is temporally associated with the use of 
the provided product, is also considered to be an adverse event.  Events such as 
medical/surgical procedures or anticipated day-to-day fluctuations of pre-existing 
conditions present at screening that do not worsen are not considered NSAE’s. 
 
All NSAE’s noted will be captured on the non-serious adverse events eCRF.  Information 
captured will include start date/time, end date/time, severity, relationship of causality to 
study drug, course of action taken, and outcome. 
 
Serious Adverse Event (SAE) 
An SAE is defined as any untoward medical occurring after signing of the informed 
consent and until cessation of the study which: 
1. results in death. 
2. is life threatening (Note: The term “life-threatening” in the definition of 
“serious” refers to an event in which the subject 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.). 
3. requires subject hospitalization or prolongation of existing hospitalization. 
4. results in persistent or significant disability/incapacity; or a congenital 
anomaly/birth defect. 
 
Medical or scientific judgment should be exercised in deciding whether 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 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definition above.  These should also be considered serious. 
SAE’s will be reported in compliance with all applicable safety reporting requirements as 
set forth in the Code of Federal Regulations.  SAE’s assessed as life threatening or death 
“possibly related to the study medication” will be reported to Clinvest, Pharmalyte 
Solutions LLC, and Sterling IRB within 24 hours of knowledge of the event by study 
staff.  All other SAE’s (such as hospitalization, disability, congenital anomaly, and an 
important medical event) will be reported to Clinvest, Pharmalyte Solutions, and Sterling 
IRB within 48 hours of knowledge of the event by study staff.  A MedWatch Form FDA 
3500A will also be completed and forwarded to Pharmalyte Solutions LLC and Clinvest.   
 
Included in the SAE Report Form will be an assessment of the causal relationship 
between the Pharmalyte Solutions LLC Materials and the SAE.  SAE’s will be followed 


1/2/15, Revised 4/20/16 
17 
 
by study staff until the event(s) have returned to normal, stabilized, or have been 
otherwise explained, for at least 2 weeks following the last dose of study drug. 
If the investigator learns of any SAEs after a subject has been discharged from the study 
and he/she considers the event reasonably related to the investigational product, the 
investigator will notify Clinvest and Pharmalyte Solutions LLC. 
 
CLINICAL SUPPLIES 
Clinical supplies will be packaged for subjects in accordance to an allocation schedule generated 
by Clinvest.   
 
LABORATORY ANALYSIS 
Laboratory specimens for the serum ionized magnesium test will be shipped to the Center for 
Biomedical and Life Sciences for analysis.  Laboratory specimens for the serum electrolytes and 
creatinine will be sent to the sites local laboratories for analysis. The collection, storage, 
shipping, and processing of the specimens will be documented. 
 
STORAGE REQUIREMENTS 
The study medication and clinical supplies must be received by a designated person at the study 
site, handled and stored safely and properly, and kept in a secured location to which only the 
investigator and designated assistants have access.  Clinical supplies and medications are to be 
dispensed only as defined in the protocol.  It is the investigator’s responsibility to keep accurate 
records of the supplies received, the amount dispensed to and returned by subjects, and the 
remaining amount at the end of the study.  Study staff should not open individual study 
medication containers prior to dispensing to the subject.   
 
Study medication received from the Sponsor will be inventoried and accounted for throughout 
the study.  Drug Accountability will be maintained for subjects randomized in the study.  Study 
staff will record the amount of study medication dispensed and amount returned at each 
appropriate office visit.  Any missing caplets or discrepancies will be addressed and reconciled 
as needed. 
 
Study medication should be kept in a secure location and stored according to the package insert.    
 
The study medication storage area at the site must be monitored by the site staff for temperature 
consistency with the acceptable storage temperature range specified on study medication 
temperature log.  Documentation of temperature monitoring should be maintained.   
 
CONFIDENTIALITY 
By signing this protocol, the investigator affirms to Clinvest information furnished to the 
investigator by Clinvest will be maintained in confidence.  Likewise, data generated by this study 
will be considered confidential by the investigator, with the exception of information included in 
a publication.   
 
The investigator also agrees that Clinvest, Institutional Review Board (IRB), or Regulatory 
Agency representatives may consult and/or copy study documents in order to verify data.  By 
signing the consent form, the subject agrees to this process.  If study documents will be 


1/2/15, Revised 4/20/16 
18 
 
photocopied during the process of verifying information, the subject will be identified by a 
unique subject number only.  Full names will be masked prior to transmission to Clinvest.   
Signing of this protocol also means the investigator agrees to treat all subject data used and 
disclosed in connection with this study in accordance will all applicable privacy laws, rules and 
regulations, including applicable provisions of Health Insurance Portability and Accountability 
Act (HIPPA).   
 
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT 
By signing the protocol, the investigator agrees to conduct the study in a diligent manner and in 
conformance with the protocol, standards of the Declaration of Helsinki under its most recent 
amendment and including Good Clinical Practice (GCP) according to the International 
Conference on Harmonisation (ICH) guidelines, and all applicable federal, state, and local laws, 
rules and regulations relating to the conduct of the clinical study.   
 
Prior to trial initiation, the investigator at each site will provide Clinvest a fully executed and 
signed Food and Drug Administration (FDA) Form 1572 and curriculum vitae (CV). 
 
The investigator also agrees to allow monitoring, audits, IRB review, and regulatory agency 
inspection of trial-related documents and procedures.  Centralized monitoring will be performed 
to verify accuracy of data entered into the electronic data capture system (EDC).   
 
Additionally, the investigator agrees not to seek reimbursement from subjects, their insurance 
providers, or from government programs for procedures included as part of the study that are 
reimbursed by Clinvest.   
 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
agency will not be allowed to conduct or work on Clinvest studies.  The investigator will 
immediately disclose in writing to Clinvest if any person who is involved in study conduct is 
debarred, or if any proceeding for debarment is pending or threatened.   
 
QUALITY CONTROL/ASSURANCE 
It is Clinvest’s responsibility for implementing and maintaining quality control and assurance 
with written SOPs to ensure the trial is conducted in compliance with GCP standards and all 
applicable federal, state, and local laws, rules, and regulations.  Appropriate tools will be 
provided to the site to facilitate quality management of the subject and continuity through the 
trial.   
 
Quality control should be applied by all parties and to each stage of subject management, 
investigational product management and data handling to ensure all data are reliable and have 
been processed correctly.  All clinical data are to be generated and processed by personnel with 
relevant clinical and GCP knowledge.  Subject generated data should be preceded with 
appropriate subject training and technical support for questions that arise during the trial.   
 
 Agreements, made by the sponsor, or their designee, with the investigator, institution and/or 
with any other parties involved with clinical trial should be in writing in a separate agreement. 
 


1/2/15, Revised 4/20/16 
19 
 
Pharmalyte Solutions LLC has transferred trial-related duties and functions to Clinvest, but 
ultimate responsibility for the quality and integrity of the trial data resides with Pharmalyte 
Solutions LLC.  The investigator agrees to be responsible for the integrity of all study conduct at 
their site.   
 
During the trial Clinvest will conduct remote monitoring and safety oversight periodically.  The 
clinical monitors may review eCRFs, central laboratory findings, etc. at intervals throughout the 
study to verify appropriate inclusion of subjects, adherence to the protocol, and completeness, 
correctness, and accuracy of eCRF entries.  Any source upload should be reviewed for privacy 
elements and removed.  Source uploads should only include the subject enrollment number as 
identifying information. 
 
The study will be registered on www.clinicaltrials.gov by Clinvest. 
   
STUDY DOCUMENTATION  
Data for this trial will be primarily collected in a web-based electronic data capture (EDC) 
REDCap platform.  The EDC access will be supplied by Clinvest with relevant training support 
to sites.  Sites will be responsible for training study subjects in the EDC system.  All data 
specified should be captured by the site personnel or subjects in the EDC system.  All eCRFs are 
to be completely filled out by personnel administering the study procedures at the time of the 
visit.  The eCRF will be considered the source document for all data collected other than 
laboratory and procedure findings, which will be uploaded into the eCRF as source.  All data 
must be reviewed and signed by the investigator or sub-investigator at the conclusion of the 
study for each subject.  The eCRFs should not be made available in any form to third parties, 
without written permission from the sponsor.   
 
It is the investigator’s responsibility for the collection and reporting of all clinical, safety, and 
laboratory data entered on the eCRF and confirmation the data is accurate, authentic, attributable, 
complete, and consistent.  The investigator or sub-investigator must sign the eCRFs within the 
EDC system to attest the information contained with the eCRF is true and causality of any safety 
information has been assessed.   
 
RECORD RETENTION 
Study documentation includes all workbooks, worksheets, forms, lab reports, logs, signature 
pages, appointment schedules, investigator correspondence, electronic data (i.e. data stored on 
cds, flash drives, etc.), and regulatory documents.  The original recording of an observation 
should be retained as the source document.   
 
1. Investigator will maintain essential documents for the conduct of a clinical study and 
any other documentation as specified by applicable regulatory requirements. 
2. Investigator will maintain a binder containing written informed consent records. 
3. Conduct of study visits will be maintained on appropriate Source Documentation/Case 
Report Forms.  Patient anonymity will be maintained on these forms by identification 
codes (i.e., subject initials and number).  The Investigator’s electronic signature will 
verify that all data entries in the CRF’s are complete and accurate. 


1/2/15, Revised 4/20/16 
20 
 
4. Investigator will maintain a Subject Identification Log.  Information such as full name 
of subject, address, contact information, and additional subject identifiers will be 
recorded.  This log will be kept confidential and not copied. 
5. Investigator will maintain a Subject Screening/Enrollment Record.  This record will 
record chronologically subjects who were seen for Visit 1, randomized at Visit 2, 
additional visits conducted during study, and completion/discontinuation information. 
6. Clinvest will maintain a Drug Assignment Log.  This log will record chronologically 
study medication received from Pharmalyte Solutions LLC, as well as medication 
returned or destroyed at the completion of the study. 
7. Investigator will maintain a Site Drug Accountability Record.  This record will record 
chronologically study medication received from the Sponsor, as well as medication 
returned or destroyed at the completion of the study.   
 
Government agency regulation and directives require all study documentation pertaining to the 
conduct of a clinical trial must be retained by the investigator for at least 2 years after the last 
approval of a marketing application in an International Conference on Harmonization (ICH) 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product.  The investigator will maintain all study documentation on file in a 
secure and safe location.  Clinvest will notify the investigator in writing when retention is no 
longer necessary.  No study records will be destroyed without prior agreement between 
Pharmalyte Solutions LLC and Clinvest.   
 
INSTITUTIONAL REVIEW BOARD 
Clinvest is responsible for obtaining IRB approval of the protocol, informed consent document, 
written information provided to the subject, recruiting material, and all other appropriate 
documents.  The trial will not be initiated until IRB approval of all trial documents.  The 
investigator will provide Pharmalyte Solutions LLC with documentation that the IRB has 
approved the protocol, informed consent, and any study-related materials to be provided to the 
subject before the study begins.  In the event an amendment is needed to any document, Clinvest 
will also be responsible for the approval of all subsequent major changes.  The investigator is 
responsible for obtaining initial and continuing review (annually if necessary) of the study by an 
IRB.  Written approval must be forwarded to Clinvest before clinical supplies will be shipped.  
For continuing studies, written approval from the IRB must be sent to Clinvest at intervals not to 
exceed 1 year.  All other appropriate reports on the progress of the study will be made to the IRB 
and the Sponsor by Clinvest in accordance with applicable governmental regulations and in 
agreement with the policy established by the Sponsor and the IRB.   
 
TRAINING 
Each approved study site will participate in a protocol training program prior to enrollment of 
any subjects in the study.  The program must be attended by the principal investigator at the site, 
and at least one research coordinator, including the coordinator who will have the lead 
responsibility for coordination of the study at the site. 
 
Comprehensive training will be provided by Clinvest to site personnel.  Training topics will 
include protocol, study design, study documents, electronic data capture system, reporting of 
AEs and pregnancy, and any other study related tasks.   


1/2/15, Revised 4/20/16 
21 
 
SAFETY MEASURES 
 
Adverse Events 
Adverse events (AEs) will be monitored throughout the study. All reported AEs 
will be documented on the appropriate eCRF. 
 
Physical Examination 
At screening and study exit, the investigator will examine the patient for any 
detectable abnormalities of the following body systems: general appearance; neck 
(including thyroid); head, eyes, ears, nose, and throat; lungs; heart/cardiovascular; 
abdomen; neurologic; extremities; back; musculoskeletal; lymphatic; skin; and 
other. The neurologic examination should be conducted to detect the presence of 
any significant sensory/motor abnormalities. A digital rectal examination is not 
required. Gynecological examinations are not required. 
 
Weight should be measured at screening, day 1, and each subsequent office visit 
using the same scale for all patients at a given investigator site when possible. 
 
Pregnancy tests for all females of childbearing potential.  Urine pregnancy testing 
will be conducted at screening, on day 1, and each subsequent office visit to 
confirm continued non-pregnant status prior to study drug administration or study 
completion.  
 
Clinical Laboratory Tests 
Blood samples will be collected for clinical laboratory testing at Visits 2-5 for all 
patients qualifying for randomization.  Non-fasting blood samples (approximately 
10 mL for Electrolytes, Creatinine, and Ionized Magnesium) should be collected 
using standard laboratory instructions and procedures provided by the 
laboratories.   
 
Vital Signs 
Vital signs will be measured at screening, day 1, and each subsequent office visit. 
Systolic and diastolic blood pressure and pulse rate over 30 seconds should be 
taken after patients have been at rest (seated) for at least 2 minutes. Blood 
pressure should be recorded in mmHg. Pulse rate should be measured in beats per 
minutes.  
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be conducted at the screening visit and each subsequent office 
visit.  The C-SSRS is a semi-structured interview designed to assess the severity 
and intensity of suicidal ideation, suicidal behavior, and non-suicidal self-
injurious behavior over a specified time period (e.g., prior year, since last visit). 
The measurement of suicidal ideation is based on 5 “yes” or “no” questions (plus 
a description if answered “yes”) arranged in order of increasing severity. If the 
patient answers “yes” to either question 1 or 2, the intensity of ideation will then 
be assessed in 5 additional questions relating to the frequency, duration, 


1/2/15, Revised 4/20/16 
22 
 
controllability, deterrents, and reasons for the most severe ideation. Suicidal 
behavior is then assessed by asking further questions to categorize the behaviors 
into actual, aborted, and interrupted attempts; preparatory behavior; and non-
suicidal self-injurious behavior. The interview is used in full only if the initial 
questions are positive; this assessment is completed at all scheduled clinic visits at 
which other clinical assessments are to be carried out.   
 
 
If any item(s) on the C-SSRS are answered with “yes”, a clinician 
investigator must review patient’s responses in order to:  
a) at screening and baseline determine patient’s study eligibility 
and potential need for referral to a mental health professional AND  
b) during the study evaluate patient’s need for appropriate medical 
management such as referral to a mental health professional. 
 
A significant risk of suicide is defined as a “yes” in answer to:  
a) questions 4 or 5 on the suicidal ideation section; OR 
b) any questions on any item in the suicidal behavior section. 
 
This must be reported as a serious adverse event and followed up accordingly.  
Additionally, if a patient responds “yes” to any of the suicidal ideation questions 1 
to 3, a clinician investigator should apply clinical judgment to determine the need 
for reporting as an adverse event or serious adverse event and the need for any 
referral. 
 
SUMMARY OF METHODS OF DATA COLLECTION 
Data required for the evaluation of the primary and some secondary measures will be recorded 
by subjects using a daily e-diary.  The following data will be collected daily with the e-diary 
(subject instructions and training for completion of the e-diary will be provided): 
• 
Estimated total duration of headache that day (if no headache, subject will report 0 
hours) 
• 
Severity of headache at the time of onset (mild, moderate, or severe) only for subjects 
who report a headache duration > 0) 
• 
Acute headache pain medication(s) usage  
• 
Study medication usage 
• 
Unusual symptoms 
 
Should a subject skip a day of e-diary entry, the subject will be able to provide the missing 
information for up to 1 calendar day.  The e-dairy should not be completed on the day of the 
office visit; the last e-dairy entry for the preceding period should be completed the day prior to 
the office visit.   
Questionnaire data required to be directly collected from subject will be obtained at each 
appropriate visit using an electronic device as defined in the protocol.  Questionnaires are to be 
completed by the subject and the answers to the questions on the questionnaires should come 
from the subject directly, not from family, friends, or the study support personnel.   
 


1/2/15, Revised 4/20/16 
23 
 
Questionnaire data required to be collected directly from clinicians will be obtained at the 
appropriate visit and recorded in the eCRF per protocol.   
 
STATISTI CAL ANALYSIS 
Subjects will be randomized 1:1 into the treatment groups.  Randomization will not include any 
type of stratification.   
 
An alpha of .05 will be used for statistical significance. All statistical tests will be two-sided.  All 
data will be analyzed using JMP (SAS Institute, Inc.).   
 
Descriptive statistics will establish baseline characteristics and adverse event frequency.  Data 
for the primary endpoint will be statistically analyzed via a repeated measures ANCOVA 
controlling for ionized serum Mg levels.  Data for each of the secondary outcome measures will 
be statistically analyzed for both within and between group changes via a 2-tailed Repeated 
Measures ANOVA and/or independent or dependent t-tests as appropriate.  All ANOVAs will be 
followed by univariate post-hoc tests as appropriate. Multiple comparison adjustments will be 
made if needed. 
 
An interim analysis will be performed when approximately 60 subjects have completed the 
study.  The results of the interim analysis may lead to stopping the study for safety or futility.  
The interim analysis will not lead to stopping the study for efficacy.  Only the primary endpoint 
and first secondary endpoint of migraine and headache day reduction will be assessed at the time 
of the interim analysis, as well as adverse events for safety purposes.   
 
 
 
Modified Intent-to-Treat Population (mITT) 
The modified intent-to-treat (mITT) population will include all randomized subjects who 
received at least one dose of study drug and obtained at least one endpoint measurement 
(mean change from baseline in the number of hours with headaches) after treating.  The 
mITT population will be used for efficacy analyses. 
 
 
Safety Population 
The safety population will include all randomized subjects who received at least one dose 
of study drug (active or placebo). 
 
A last observation carried forward (LOCF) method will be utilized to impute missing values for 
subjects continuing in the study, but missing values for this analysis.  This type of imputation 
replaces the missing value with the last observation value obtained.  Baseline observation carried 
forward (BOCF) method will be used if a subject discontinues the study.  Thus, if a subject has a 
missing value at month 2 due to discontinuation, the baseline value will be utilized and the 
subject will be considered a non-responder.   
 
PRIMARY ENDPOINT 
To compare the mean change from baseline in the frequency of migraine headache days per 28-
day period ending with the cessation of treatment period month 3 in subjects treated with 
MLD10 versus placebo.  
 


1/2/15, Revised 4/20/16 
24 
 
A migraine headache day will be defined as a calendar day (00:00 to 23:59) with 4 or more hours 
of migraine headache, fulfilling ICHD-3 beta criteria, and/or any headache of any duration with 
the use of migraine-specific acute medications(s) (i.e. ergot alkaloids, ergot combinations, 
opioids, triptans, combination analgesics [simple analgesics combined with opioids or barbiturate 
with or without caffeine]).  
 
SECONDARY ENDPOINTS  
1. To compare change from baseline of subjects treated with MLD10 versus placebo on 
the following parameters during or after a 3 month treatment period: 
• 
the frequency of headache days 
• 
the average headache duration after 1, 2, and 3 months of treatment 
• 
reduction of pain severity at the time of headache onset  
• 
the use of acute medications after 1, 2, and 3 months of treatment 
• 
Migraine Disability Assessment Scale (MIDAS) scores at Visits 2 and 5 
• 
Subject Global Impression of Change (SGIC) at Visit 5 
• 
Physician Global Impression of Change (PGIC) at Visit 5 
2. To assess the safety and tolerability of magnesium-L-lacate-dihydrate versus placebo 
in migraine headache subjects through the comparison of adverse events. 
 
EXPLORATORY ENDPOINTS  
To compare the change from baseline of subjects treating with MLD10 versus placebo on the 
following parameters during a 3 month treatment period. 
• 
migraine with aura days 
• 
serum ionized magnesium 
 
SAFETY ENDPOINTS 
Safety assessments will include: 
• 
adverse events 
 
COLLECTION AND DERIVATION OF ENDPOINTS 
Data required for the evaluation of endpoints will be recorded for the duration of the study using 
electronic data capture and included subject and clinician reported outcomes.  
 
Following visit 2, subsequent visits will occur every 28 days for 3 months.  However, in practice, 
there may or may not be an exact 28-day duration between 2 consecutive visits.  For data 
analysis purposes, the number of migraine headache days during the first 28 continuous days of 
the run-in period will serve at the “baseline” for calculating change from baseline for 28-day 
periods subsequent to each office visit.  If the run-in period (starting with the screening visit and 
preceding the day before visit 2) exceeds 28 days, the run-in period will include the last 28-days.  
In order to be randomized, a subject must meet 80% diary completion compliance (22 days 
recorded unless otherwise approved by the Sponsor and/or Clinvest). 
 
 
Primary Efficacy Variable 
The primary efficacy variable is the mean change from baseline in the frequency of 
migraine headache days per 28-day period ending with the cessation of treatment period 
month 3 in subjects treated with MLD10 versus placebo. This variable is derived from 


1/2/15, Revised 4/20/16 
25 
 
the e-dairy.  It is based on the count of days with migraine headaches, fulfilling ICHD-3 
beta criteria, and/or headaches of any duration with the use of migraine-specific acute 
headache medication(s).  The primary time point is treatment month 3, encompassing the 
last 28-day period before study end.   
 
 
Secondary Efficacy Variables 
• 
Change from baseline in the frequency of headache days per 28-day period.  
This variable will be derived from daily e-diary reports.  It will be based on 
the count of days with headaches.  
• 
Change from baseline in the total cumulative hours of headache per 28-day 
period.  This variable will be derived from daily e-diary reports.  It will be 
based on the sum of total headache duration for days with any headache.   
• 
Change from baseline in the average pain severity at time of onset compared 
to each 28-day period.  This variable will be derived from the daily e-diary 
reports.   
• 
Reduction from baseline in the total number of acute headache pain 
medications used.  This variable will be derived from the daily e-diary reports.  
• 
Change from baseline in the total MIDAS score.  This variable will be derived 
from the subject questionnaire. 
• 
SGIC score at the end of treatment.  This variable will be derived from the 
subject questionnaire. 
• 
PGIC score at the end of treatment.  This variable will be derived from the 
clinician reports.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


1/2/15, Revised 4/20/16 
26 
 
APPENDIX 1 
Proposed Revised International Headache Society Criteria for  
Migraine Without and With Aura 
 
Headache Classification Committee: J Olesen, et al. The International Classification of 
Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013, 33:629-808. 
 
1.1 Migraine without aura 
Description: 
Recurrent headache disorder manifesting in attacks lasting 4-72 hours. 
 
Diagnostic criteria: 
A. At least five attacks1 fulfilling criteria B–D 
B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) 
C. Headache has at least two of the following four characteristics: 
1. unilateral location 
2. pulsating quality 
3. moderate or severe pain intensity 
4. aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing 
    stairs) 
D. During headache at least one of the following: 
1. nausea and/or vomiting 
2. photophobia and phonophobia 
E. Not better accounted for by another ICHD-3 diagnosis. 
 
1.2 Migraine with aura 
Description: 
Recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or other central 
nervous system symptoms that usually develop gradually. 
 
Diagnostic criteria: 
A. At least two attacks fulfilling criteria B and C 
B. One or more of the following fully reversible aura symptoms: 
1. visual 
2. sensory 
3. speech and/or language 
4. motor 
5. brainstem 
6. retinal 
C. At least two of the following four characteristics: 
1. at least one aura symptom spreads gradually over _5 minutes, and/or two or more symptoms 
    occur in succession 
2. each individual aura symptom lasts 5-60 minutes 
3. at least one aura symptom is unilateral 
4. the aura is accompanied, or followed within 60 minutes, by headache 
D. Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has 
    been excluded. 


1/2/15, Revised 4/20/16 
27 
 
APPENDIX II 
Proposed Revised International Headache Society  
Criteria for Medication-Overuse Headache 
 
Headache Classification Committee: J Olesen, et al. The International Classification of 
Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013, 33:629-808. 
Description: 
Headache occurring on 15 or more days per month developing as a consequence of regular 
overuse of acute or symptomatic headache medication (on 10 or more, or 15 or more days per 
month, depending on the medication) for more than 3 months. It usually, but not invariably, 
resolves after the overuse is stopped. 
 
General comment: 
In the criteria set out below for the various subtypes, the specified numbers of days of 
medication use considered to constitute overuse are based on expert opinion rather than on 
formal evidence. 
 
Diagnostic criteria: 
A. Headache occurring on _15 days per month in a patient with a pre-existing headache disorder 
B. Regular overuse for >3 months of one or more drugs that can be taken for acute and/or 
symptomatic treatment of headache 
C. Not better accounted for by another ICHD-3 diagnosis. 
 
 

SAP_001.pdf: 
Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 1 of 13 
Clinvest Research, LLC. 
Statistical Analysis Plan 
 
Study Title: 
A Multicenter, Randomized, Double-blind, Placebo-
controlled Study Evaluating the Efficacy and Safety of 
MLD10 in the Prevention of Migraine Headache in 
Adults 
Protocol Number: 
MLD10-002 
Sponsor: 
Pharmalyte Solutions, LLC. 
580 Commerce Street  
Suite 100 
Southlake, TX 76092 
Medical Monitor: 
Timothy R. Smith MD, RPh, FACP 
4350 S. National Ave. 
Suite C100 
Springfield, MO 65810 
Phone: (417) 883-7889 
Email: timothy.smith.md@gmail.com 
Trial Statistician 
Jim Sly, MS 
4350 S. National Ave. 
Suite C100 
Springfield, MO 65810 
Phone: (417) 841-3673 
Email: jsly@clinvest.com 
SAP Authors 
Jim Sly, MS and Heather Manley, MS 
Date of Original SAP 
(Version No. 1.0): 
10-Dec-2014 
Date of Final SAP 
(Version No. 1.1): 
29-Jun-2017 
Approved by: 
Date: 
Signature: 
 
 
 
  
 
 
 
 
 
 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 2 of 13 
Confidential Information 
 
The information contained in this document is the property or under the control of Clinvest 
Research, LLC., and is provided to you in confidence as an Investigator, potential Investigator, 
or consultant for review by you, your staff and applicable Institutional Review Board.  You shall 
not disclose this information to others without prior written authorization from Clinvest 
Research, LLC., except to the extent necessary to obtain informed consent from those persons to 
whom the drug may be administered, and except as may be required by federal, state, or local 
laws or regulations. 
 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 3 of 13 
Table of Contents 
1 
Abbreviations and Definitions ......................................................................................... 4 
2 
Introduction ...................................................................................................................... 5 
2.1 
Study Purpose ............................................................................................................ 5 
2.2 
Summary of Study Design ........................................................................................ 5 
2.3 
Power Analysis........................................................................................................... 5 
2.4 
Inclusion-Exclusion Criteria .................................................................................... 5 
2.5 
Randomization and Blinding ................................................................................... 7 
2.6 
Study Procedures....................................................................................................... 8 
3 
Analysis Populations......................................................................................................... 8 
3.1 
Full Analysis Population ........................................................................................... 8 
3.2 
Modified Intent-to-Treat Population (mITT) ......................................................... 8 
3.3 
Safety Population....................................................................................................... 8 
4 
Endpoints ........................................................................................................................... 9 
4.1 
Primary Endpoint ..................................................................................................... 9 
4.2 
Secondary Endpoints ................................................................................................ 9 
4.3 
Exploratory Endpoints ............................................................................................. 9 
4.4 
Safety Endpoints ........................................................................................................ 9 
5 
Collection and Derivation of Endpoint Variables ......................................................... 9 
5.1 
Primary Efficacy Variable...................................................................................... 10 
5.2 
Secondary Efficacy Variables ................................................................................ 10 
5.3 
Exploratory Variables............................................................................................. 11 
5.4 
Safety Variables ....................................................................................................... 11 
6 
Missing Data .................................................................................................................... 12 
7 
Timing of Final Analyses ............................................................................................... 12 
8 
Efficacy Analyses ............................................................................................................ 12 
8.1 
Primary Efficacy Analysis ...................................................................................... 12 
8.2 
Secondary Efficacy Analyses .................................................................................. 12 
8.2.1 
Frequency of headache days .............................................................................. 12 
8.2.2 
Headache duration after 1, 2, and 3 months of treatment .................................. 12 
8.2.3 
Pain severity at the time of headache onset ....................................................... 13 
8.2.4 
Acute medications after 1, 2, and 3 months of treatment .................................. 13 
8.2.5 
Migraine Disability Assessment Scale (MIDAS) scores at Visits 2 and 5 ........ 13 
8.2.6 
Subject Global Impression of Change (SGIC) at Visit 5 ................................... 13 
8.2.7 
Physician Global Impression of Change (PGIC) at Visit 5 ............................... 13 
8.3 
Exploratory Efficacy Analysis................................................................................ 13 
9 
Safety Analysis ................................................................................................................ 13 
9.1 
Adverse Events ........................................................................................................ 13 
 
 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 4 of 13 
1 
Abbreviations and Definitions 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
BOCF 
Baseline Observation Carried Forward 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EDC 
Electronic Data Capture 
ICHD 
International Classification of Headache 
Disorders 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary of Regulatory Affairs 
MIDAS 
Migraine Disability Assessment 
mITT 
Modified Intent-to-Treat 
MO 
Medication Overuse 
MOH 
Medication Overuse Headache 
NSAE 
Non-Serious Adverse Event 
PGIC 
Physician Global Impression of Change 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SGIC 
Subject Global Impression of Change 
 
 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 5 of 13 
2 
Introduction 
2.1 Study Purpose 
• 
To evaluate the daily use of MLD10 and placebo for the treatment of migraine, as 
measured by the change from baseline in the number of migraine headache days of 
subjects treated for 3 months. 
• 
To compare daily use of MLD10 and placebo as measured by: 
- 
change in the quantitative and qualitative aspects of migraine headaches from 
baseline, during treatment, and at the conclusion of a 3-month treatment period. 
- 
safety and tolerability measures in migraine headache subjects through the 
monitoring of adverse events (AEs) and clinical chemistry values. 
2.2 Summary of Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel study of MLD10 
for the prevention of migraine headache.  The study population will consist of approximately 142 
male and female subjects between 18 and 65 years of age with frequent episodic migraine as 
defined by International Classification of Headache Disorders beta (ICHD-3) criteria. Subjects 
agreeing to participate in the study and meet the entry criteria assessed at the screening visit, will 
begin a 28-day baseline period to confirm their diagnosis, as well as establish baseline migraine 
characteristics.  During this baseline period, subjects will continue treating their migraines as 
usual, simply recording the information in a daily headache diary.  Subjects who, after 
completing the baseline, continue to meet entrance criteria will be eligible to enter into the 
treatment phase and be randomized according to the Clinvest generated randomization schedule.  
Approximately 142 subjects (71 subjects per arm) will be randomized and enter the treatment 
phase receiving MLD10 or placebo in a 1:1 design at a maximum of 8 US sites. Two MLD10 
(243 mg of elemental magnesium) or placebo caplets will be taken twice daily for a total daily 
dose of 486 mg. Diary assessments will collect study medication adherence, pain severity, 
headache symptoms, acute medication usage, and unusual symptoms. Serum samples will be 
collected and analyzed for ionized Mg, electrolytes, and creatinine.  
2.3 Power Analysis 
A power analysis, using GPower Version 3.1.7, indicated a total sample size of 128 subjects 
would be needed to detect a medium effect with 80% power using an analysis of covariance 
(ANCOVA) test to include fixed effects, main effects, and interactions with alpha being .05.  
Given an estimated 10% early termination rate, a total estimated sample size of 142 subjects is 
needed.   
2.4 Inclusion-Exclusion Criteria 
Inclusion Criteria 
Subjects must meet the following inclusion criteria: 
1. male or female, in otherwise good health, 18 to 65 years of age.   
2. history of frequent episodic migraine (3-14 migraine days per month) (with or 
without aura) according to the ICHD-3 beta for at least 3 months.  
3. onset of migraine before age 50.  
4. stable history of migraine at least 3 months prior to screening. 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 6 of 13 
5. not currently taking a migraine preventive or has been taking preventive for at least 
30 days prior to screening and agrees to not start, stop, or change medication and/or 
dosage during the study period. 
6. if female of childbearing potential, has a negative urine pregnancy test at Visits 1-5 
and uses, or agrees to use, for the duration of the study, a medically acceptable form 
of contraception as listed:  
• 
complete abstinence from intercourse from 2 weeks prior to administration of 
study drug, throughout the study, and for 7 days after completion or 
premature discontinuation from the study; surgically sterile (hysterectomy or 
tubal ligation or otherwise incapable of pregnancy); sterilization of male 
partner when in a monogamous relationship; intrauterine device with 
published data showing lowest expected failure rate is less than 1% per year; 
double barrier method (i.e., 2 physical barriers OR 1 physical barrier plus 
spermicide) for a least 1 month prior to Visit 1 and throughout study; or 
hormonal contraceptives for at least 3 months prior to Visit 1 and throughout 
study. 
7. completion of online diary must be ≥ 80% compliance, unless otherwise approved by 
the Sponsor and/or Clinvest.   
 
Exclusion Criteria 
Subjects must NOT meet any of the following exclusion criteria: 
1. unable to understand the study requirements, the informed consent, or complete 
headache records as required per protocol. 
2. pregnant, actively trying to become pregnant, or breast-feeding. 
3. diagnosed with ICHD-3 beta criteria for Chronic Migraine within 3 months prior to 
screening, at the time of screening, and/or during the baseline period. 
4. experienced the following migraine variants: basilar migraine, aura without headache, 
familial hemiplegic migraine, complicated migraine, ophthalmoplegic migraine and 
retinal migraine within the last year. 
5. history of medication overuse headache (MOH) in the 3 months prior to study 
enrollment or during the baseline phase.  
6. history of medication overuse (MO) of ergotamines, triptans, opioids, analgesics, 
NSAIDS and combination therapies, as defined by ICHD-3 beta criteria and/or MO 
during baseline period. 
7. history of substance abuse and/or dependence, in the opinion of the Investigator. 
8. history of impaired renal function that, in the investigator’s opinion, contraindicates 
participation in this study. 
9. unstable neurological condition or a significantly abnormal neurological examination 
with focal signs or signs of increased intracranial pressure. 
10. suffers from a serious illness, or an unstable medical condition, one that could require 
hospitalization, or could increase the risk of adverse events. 
11. has significant risk of suicide, defined as a “yes” answer to any of the following 
questions on the Columbia-Suicide Severity Rating Scale (C-SSRS), either at the 
screening visit (when assessing the prior 12 months) or at visit 2 (when assessing time 
since the screening visit): 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 7 of 13 
a. Questions 4 or 5 on the suicidal ideation section 
b. Any question on any item in the suicidal behavior section 
12. any psychiatric disorder with psychotic features, and/or any other psychiatric disorder 
not stable or well controlled, that would interfere in their ability to complete study 
activities.  
13. hypersensitivity, intolerance, or contraindication to the use of magnesium L-lactate 
dehydrate or any of its components. 
14. received any investigational agents within 30 days prior to Visit 1. 
15. plans to participate in another clinical study at any time during this study. 
2.5 Randomization and Blinding 
Eligible subjects will be randomized 1:1 to receive magnesium L-lactate dehydrate (243 mg of 
elemental mg++ BID for a total of 486mg daily) or placebo at Visit 2. A 2-block randomization 
schedule will be created prior to study initiation using www.randomization.com and uploaded 
into the EDC system. Randomization will not include any type of stratification. Randomization 
will include attesting in the EDC the subject meets inclusion/exclusion criteria and is appropriate 
for the study. After this determination is made, the subject will be assigned to an auto populated 
drug kit number which will display in the source document in the EDC. 
At randomization (Visit 2), neither the subject nor the investigator will be aware to which 
treatment group the subject has been assigned.  If needed, for safety and proper treatment of the 
subject, the investigator can unblind the subject’s treatment assignment to determine which 
treatment has been assigned and institute appropriate follow-up care.  When possible, Clinvest 
should be notified prior to unblinding study medication.    
 
Individual unblinding envelopes are shipped with study medication.  Each study medication kit 
has a corresponding unblinding envelope.  Unblinding will include matching the kit and 
unblinding envelope with the subject drug number. 
 
To unblind a subject without breaking the blind for remaining subjects’ treatment the following 
instructions described below will be followed: 
 
• 
Obtain the security envelope containing the unblinding envelopes. 
• 
Remove the unblinding envelope with the study drug number corresponding with the 
study medication kit dispensed to the subject. 
• 
Break the seal of the unblinding envelope and remove the subjects’ treatment label. 
• 
Return the subjects’ treatment label to the unblinding envelope. 
• 
Return the unblinding envelope to the security envelope. 
• 
Document on the unblinding form located in the eAdmin Binder.  
• 
Email copy of unblinding form to study@clinvest.com within 24 hours of unblinding. 
• 
Complete and email or fax the Sterling Institutional Review Board (IRB), unanticipated 
problem report form, to Sterling IRB within 10 business days of unblinding.  
 
 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 8 of 13 
2.6 Study Procedures 
 
Screening 
Randomization 
Treatment 
Visit 1 
Day 0 
 
Visit 2 
Day 29 
(+/- 3) 
Visit 3 
Day 58 
(+/- 3) 
Visit 4 
Day 87 
(+/- 3) 
Visit 5 
Day 116 
(+/- 3) 
Informed Consent 
X 
 
 
 
 
Physical/Neurological Exam 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
Verify Inclusion/Exclusion 
X 
X 
 
 
 
Subject Randomization 
 
X 
 
 
 
Medical History 
X 
 
 
 
 
Migraine History 
X 
 
 
 
 
Medication History 
X 
 
 
 
 
Update Medications 
 
X 
X 
X 
X 
Urine Pregnancy Test  
X 
X 
X 
X 
X 
SGIC 
 
 
 
 
X 
PGIC 
 
 
 
 
X 
Dispense Study Medication 
 
X 
X 
X 
 
Drug Accountability 
 
 
X 
X 
X 
Headache Diary 
X 
X 
X 
X 
 
Review Diary 
 
X 
X 
X 
X 
Collect Adverse Events 
 
X 
X 
X 
X 
Administer C-SSRS 
X 
X 
X 
X 
X 
Administer MIDAS 
 
X 
 
 
X 
Serum Electrolytes & 
Creatinine  
 
X 
X 
X 
X 
Serum Ionized Mg 
 
X 
X 
X 
X 
3 
Analysis Populations 
3.1 Full Analysis Population 
All subjects who were randomized. The full analysis population will be used for 
demographic and adverse event reporting. 
3.2 Modified Intent-to-Treat Population (mITT) 
The modified intent-to-treat (mITT) population will include all randomized subjects who 
received at least one dose of study drug and obtained at least one endpoint measurement (mean 
change from baseline to treatment month, in the number of migraine headaches) after treating. 
The mITT population will be used for all efficacy analyses. 
3.3 Safety Population 
The safety population will include all randomized subjects who received at least one dose of 
study drug (active or placebo). The safety population will be used for all safety endpoints. 
 
 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 9 of 13 
4 
Endpoints 
4.1 Primary Endpoint 
To compare the mean change from baseline in the frequency of migraine headache days per 28-
day period ending with the cessation of treatment period month 3 in subjects treated with 
MLD10 versus placebo.  
 
4.2 Secondary Endpoints  
1. To compare change from baseline of subjects treated with MLD10 versus placebo on the 
following parameters during or after a 3-month treatment period: 
1. the frequency of headache days 
2. the average headache duration after 1, 2, and 3 months of treatment 
3. reduction of pain severity at the time of headache onset  
4. the use of acute medications after 1, 2, and 3 months of treatment 
5. Migraine Disability Assessment Scale (MIDAS) scores at Visits 2 and 5 
6. Subject Global Impression of Change (SGIC) at Visit 5 
7. Physician Global Impression of Change (PGIC) at Visit 5 
2. To assess the safety and tolerability of magnesium-L-lacate-dihydrate versus placebo in 
migraine headache subjects through the comparison of adverse events. 
4.3 Exploratory Endpoints  
To compare the change from baseline of subjects treating with MLD10 versus placebo on the 
following parameters during a 3-month treatment period. 
• 
serum ionized magnesium 
4.4 Safety Endpoints 
Safety assessments will include: 
• 
adverse events 
5 
Collection and Derivation of Endpoint Variables 
Data required for the evaluation of endpoints will be recorded for the duration of the study using 
electronic data capture (EDC) and include subject and clinician reported outcomes. Subjects will 
record data into the web-based EDC using a daily eDiary. Subjects will be provided instruction 
and training regarding daily eDiary entry and compliance requirements. 
 
Clinic visits will be scheduled to occur every 28 days throughout the study; however, in practice, 
there may or may not be an exact 28-day duration between 2 consecutive visits. For this reason, 
subjects will be given access to 31 days of eDiary to complete between clinic visits. For the 
collection and derivation of endpoint variables and analyses, subject’s eDiary information will be 
used as follows: 
 
• 
eDiary information entered during the first 28 continuous days of the run-in period 
will serve as the “baseline” for calculating change from baseline for 28-day periods 
subsequent to each office visit.  If the run-in period (starting with the screening visit 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 10 of 13 
and preceding the day before visit 2) exceeds 28 days, the run-in period will include 
the last 28-days. 
• 
If a subject enters more than 28 days of eDiary information between clinic visits 
during the treatment phase of the study, the last (most recent) 28 eDiary entries will 
be used for analyses. For example, if a subject has a duration of 31 days between 
Visit 2 and Visit 3, and the subject entered eDiary information for all 31 days, the last 
28 days of eDiary information will be used to calculate and derive endpoint variables, 
with the first three eDiary entries being discarded from the analysis datasets. 
• 
Each subject-entered eDiary record will be used and analyzed as a separate study day, 
regardless of the subject’s entered diary date (value entered from the subject as the 
date of diary data), actual date of eDiary entry (EDC timestamp), or perceived 
duplicate entry. 
 
5.1 Primary Efficacy Variable 
The primary efficacy variable is the mean change from baseline in the frequency of migraine 
headache days per 28-day period ending with the cessation of treatment period month 3 in 
subjects treated with MLD10 versus placebo. The time point for this variable is baseline to 
treatment month 3, encompassing the last 28-day period before study end. This variable is 
derived from the e-dairy and is based on the count of days with migraine headaches. Migraine 
headaches are defined as a calendar day (00:00 to 23:59) with 4 or more hours of migraine 
headache, fulfilling ICHD-3 beta criteria, and/or any headache of any duration with the use of 
migraine-specific acute medications(s) (i.e. ergot alkaloids, ergot combinations, opioids, triptans, 
combination analgesics [simple analgesics combined with opioids or barbiturate with or without 
caffeine]). Headache duration for the determination of migraine will be derived from the eDiary 
Yes/No question “Did you have at least four (4) consecutive hours of headache?”. 
 
5.2 Secondary Efficacy Variables 
1. The frequency of headache days. This secondary efficacy variable is the mean change 
from baseline in the frequency of headache days per 28-day period ending with the 
cessation of treatment period month 3 in subjects treated with MLD10 versus placebo. 
The time point for this variable is baseline to treatment month 3, encompassing the last 
28-day period before study end. This variable is derived from the e-dairy and is based on 
the count of days with headaches. The determination of a headache day will be derived 
from the eDiary Yes/No question “Did you experience a headache of any severity 
yesterday?”. 
2. The average headache duration after 1, 2, and 3 months of treatment. This secondary 
efficacy variable is the mean change from baseline in the duration of headaches per each 
28-day period ending with the cessation of treatment period month 3 in subjects treated 
with MLD10 versus placebo. The time point for this variable is baseline to treatment 
month 1, 2, and 3. This variable is derived from the eDiary and is based on the difference 
(measured in minutes) between the subject-reported start and stop time for any headache 
days. eDiary records where there are subject-entered data errors (e.g., a headache stop 
time recorded as prior to the headache start time) will be excluded from analysis. 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 11 of 13 
3. Reduction of pain severity at the time of headache onset after 1, 2, and 3 months of 
treatment. This secondary efficacy variable is the mean change from baseline in pain 
severity of headaches per each 28-day period ending with the cessation of treatment 
period month 3 in subjects treated with MLD10 versus placebo. The time point for this 
variable is baseline to treatment month 1, 2, and 3. Pain severity will be determined from 
the eDiary question “What was the greatest severity that your headache reached?” and 
be coded as: 1 = Mild, 2 = Moderate, 3 = Severe. 
4. The use of acute medications after 1, 2, and 3 months of treatment. This secondary 
efficacy variable is the mean change from baseline in the total number of acute headache 
pain medications used per each 28-day period ending with the cessation of treatment 
period month 3 in subjects treated with MLD10 versus placebo. The time point for this 
variable is baseline to treatment month 1, 2, and 3. This variable is derived from the 
eDiary and is calculated by summing all entries from the eDiary questions “Number of 
times medication was taken?” 
5. Migraine Disability Assessment Scale (MIDAS) scores at Visits 2 and 5. This secondary 
efficacy variable is the mean change from Visit 2 and Visit 5 (or Early Termination Visit) 
total MIDAS scores in subjects treated with MLD10 versus placebo. The time point for 
this variable is beginning of randomization to end of treatment month 3 (end of study). 
This variable is derived from the validated scoring of the MIDAS questionnaires at Visit 
2 and end of study. 
6. Subject Global Impression of Change (SGIC) at Visit 5. This variable will be derived 
from the subject questionnaire at the end of study, “Since the beginning of the study, do 
you believe you are now” and be coded as: -3 = Extremely Worse, -2 = Moderately 
Worse, -1 = Somewhat Worse, 0 = No Change, 1 = Somewhat Better, 2 = Moderately 
Better, 3 = Extremely Better. 
7. Physician Global Impression of Change (PGIC) at Visit 5. This variable will be derived 
from the physician question at the end of study, “Since the beginning of the study, do you 
believe the subject is now” and be coded as: -3 = Extremely Worse, -2 = Moderately 
Worse, -1 = Somewhat Worse, 0 = No Change, 1 = Somewhat Better, 2 = Moderately 
Better, 3 = Extremely Better. 
5.3 Exploratory Variables 
Serum ionized magnesium levels. This exploratory variable is the mean change from baseline in 
serum ionized magnesium levels per 28-day period ending with the cessation of treatment period 
month 3 in subjects treated with MLD10 versus placebo. The time point for this variable is 
baseline to treatment month 1, 2, and 3. This variable is derived by taking the mean of two 
analyzed sample values at each visit (Visits 2, 3, 4, and 5/ET). 
 
5.4 Safety Variables 
Non-Serious adverse events (NSAEs) and Serious adverse events (SAEs) will be recorded in the 
EDC system by study staff and/or physicians and be coded to Medical Dictionary of Regulatory 
Affairs (MedDRA) preferred terms by the Clinvest Research Data Management team. 
 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 12 of 13 
6 
Missing Data 
A last observation carried forward (LOCF) method will be utilized to impute missing values for 
all mITT population subjects with missing values for a specific analysis.  This type of imputation 
replaces the missing value with the last observation value obtained.  Baseline observation carried 
forward (BOCF) method will be used if a subject discontinues the study prior to receiving at 
least one dose of study drug and obtaining at least one endpoint measurement (mean change 
from baseline in the number of migraine headaches) after treating.  Thus, if a subject has a 
missing value at month 2 (Treatment Month 1) due to discontinuation, the baseline value will be 
utilized and the subject will be considered a non-responder. If no prior observation is available to 
use for BOCF or LOCF, the mean value of all eligible subjects for that particular analysis will be 
imputed for the missing value. 
7 
Timing of Final Analyses  
The final analyses will be performed after: 
• 
the finalization and approval of this statistical analysis plan (SAP) document 
• 
all randomized subjects have exited the study by completing Visit 5 or early 
terminated prior to completion 
• 
the EDC database has been locked 
8 
Efficacy Analyses 
All statistical tests will be two-tailed, and an alpha of .05 will be used for statistical significance. 
All analyses of variance (ANOVAs) will be followed by univariate post-hoc tests as appropriate. 
Multiple comparison adjustments will be made if needed. 
 
8.1 Primary Efficacy Analysis 
Data for the primary endpoint will be statistically analyzed via a repeated measures ANCOVA 
controlling for Visit 2 ionized serum Mg levels. The analysis will compare the mean change in 
the frequency of migraine headache days from baseline to treatment month 3 in subjects treated 
with MLD10 versus placebo using Visit 2 ionized serum Mg levels as the covariate. 
8.2 Secondary Efficacy Analyses 
8.2.1 Frequency of headache days 
Data for this secondary endpoint will be statistically analyzed via a repeated measures ANOVA. 
The analysis will compare the mean change in the frequency of headache days from baseline to 
treatment month 3 in subjects treated with MLD10 versus placebo. 
8.2.2 Headache duration after 1, 2, and 3 months of treatment 
Data for this secondary endpoint will be statistically analyzed via a repeated measures ANOVA. 
The analysis will compare the mean change in headache duration (measured in minutes) from 
baseline to treatment months, 1, 2, and 3 in subjects treated with MLD10 versus placebo. 
 


Protocol No.: MLD10-002 
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of MLD10 in the Prevention of 
Migraine Headache in Adults 
Date: 29-Jun-2017 
 
Version No.: 1.1 
CONFIDENTIAL 
Page 13 of 13 
8.2.3 Pain severity at the time of headache onset 
Data for this secondary endpoint will be statistically analyzed via a repeated measures ANOVA. 
The analysis will compare the mean change in headache pain severity from baseline to treatment 
months, 1, 2, and 3 in subjects treated with MLD10 versus placebo. 
8.2.4 Acute medications after 1, 2, and 3 months of treatment 
Data for this secondary endpoint will be statistically analyzed via a repeated measures ANOVA. 
The analysis will compare the mean change in the total number of acute headache pain 
medications used from baseline to treatment months, 1, 2, and 3 in subjects treated with MLD10 
versus placebo. 
8.2.5 Migraine Disability Assessment Scale (MIDAS) scores at Visits 2 and 5 
Data for this secondary endpoint will be statistically analyzed via a repeated measures ANOVA. 
The analysis will compare the mean change in total MIDAS scores from Visit 2 (randomization) 
to Visit 5 (end of study) in subjects treated with MLD10 versus placebo. 
8.2.6 Subject Global Impression of Change (SGIC) at Visit 5 
Data for this secondary endpoint will be statistically analyzed via an independent samples t-test. 
The analysis will compare the mean difference of SGIC between subjects treated with MLD10 
versus placebo. 
8.2.7 Physician Global Impression of Change (PGIC) at Visit 5 
Data for this secondary endpoint will be statistically analyzed via an independent samples t-test. 
The analysis will compare the mean difference of PGIC between subjects treated with MLD10 
versus placebo. 
 
8.3 Exploratory Efficacy Analysis 
Data for this exploratory endpoint will be statistically analyzed via a repeated measures 
ANOVA. The analysis will compare the mean change in serum ionized magnesium levels from 
baseline to treatment months, 1, 2, and 3 in subjects treated with MLD10 versus placebo. 
9 
Safety Analysis 
9.1 Adverse Events 
Data for this safety endpoint will be statistically analyzed via an independent samples t-test. The 
analysis will compare the mean difference of total adverse events between subjects treated with 
MLD10 versus placebo.