Safety and Efficacy Study of Recombinant Human Insulin-Like Growth Factor-I/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 (rhIGF-I/rhIGFBP-3) In Myotonic Dystrophy Type 1

Study Overview
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Brief Summary
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To investigate the effects of rhIGF-I/rhIGFBP-3 treatment for 24 weeks on endurance, ambulation, cognitive functioning, insulin resistance, lipid levels, muscle function and strength, pain, gastrointestinal functioning, and quality of life endpoints in DM1 patients

Detailed Description
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Efficacy Measures: Endurance, Ambulation, Cognitive function, Insulin resistance, Cholesterol and triglycerides, Muscle function and strength, Pain, Gastrointestinal function, Quality of life MINIMUM INCLUSION CRITERIA A diagnosis of DM1, confirmed by DM1 genetic mutation Age 21 to 65 years (inclusive) Ability to walk 30 feet - assistance with cane and/or leg bracing permitted Able to self-administer study medication by subcutaneous injection or caregiver is available to administer study medication

Official Title
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A Placebo Controlled, Randomized, Double-Blind Phase II Clinical Trial to Evaluate Tolerability, Safety and Efficacy Endpoints After Administration of Recombinant Human Insulin-Like Growth Factor-I/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 (rhIGF-I/rhIGFBP-3) for 24 Weeks in Adults With Myotonic Dystrophy Type 1

Conditions
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Myotonic Dystrophy Type 1

Intervention / Treatment
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* Drug: rhIGF-I/rhIGFBP-3
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (list is not inclusive): A diagnosis of DM1, confirmed by DM1 genetic mutation Ability to walk 30 feet - assistance with cane and/or leg bracing permitted Able to self-administer study medication by subcutaneous injection or caregiver is available to administer study medication Exclusion Criteria (list is not inclusive): Congenital DM1 Weight greater than 100 kg or body mass index greater than 30 kg/m2 Prior treatment with glucocorticoids, anabolic steroids, testosterone, growth hormone, investigational agent within 60 days of screening Current diagnosis or history of malignancy expect for surgically cured skin cancer or pilomatricoma Changes in lipid lowering medications during the 3 months prior to screening Diaphragmatic weakness such that patients are unable to tolerate the supine position, or swallowing impairment such that patients are unable to maintain nutrition without use of gastrostomy. Major psychiatric illness (major depression, bipolar disorder or schizophrenia) within twelve months of screening History of non-compliance with other therapies

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rhIGF-I/rhIGFBP-3<br> | Drug: rhIGF-I/rhIGFBP-3<br>* 1.0 mg/kg rhIGF-I/rhIGFBP-3 or placebo daily, subcutaneous injections from baseline through the last day of the end of study visit.<br>|
| Placebo Comparator: Placebo<br> | Drug: placebo<br>* 1.0 mg/kg rhIGF-I/rhIGFBP-3 or placebo daily, subcutaneous injections from baseline through the last day of the end of study visit.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in Distance Walked as Assessed by the Six-minute Walk Test (6MWT) Distance | The 6MWT measured the distance in meters that participants were able to walk over a total of six minutes. After a 10 minute resting period, the participants completed the 6MWT on a hard, flat surface at baseline and at Week 24. | Baseline and Week 24 | 
| Change From Baseline in Daily Step Count | The number of steps taken per day was measured using a step activity monitor for 7 days at baseline and again at Week 24. Change from baseline scores were measured where a negative change from baseline indicates a decrease in the number of daily steps. | Baseline and Week 24 | 
| Peak Activity Index: Change From Baseline in Number of Steps Walked Per Minute During the 30 Minute Period of Fastest Walking | The peak activity index measures the number of steps walked in the 30 minutes of fastest walking that occurred in a 24 hour period. This was measured using a step activity monitor for 7 days at baseline and again at Week 24. Change from baseline scores were measured where a positive change from baseline indicates an improvement in the number of steps walked during the 30 minute period of fastest walking. | Baseline and Week 24 | 
| Sustained Activity Index: Change From Baseline in the Highest Number of Steps Walked Per Minute Over 20 Minutes of Activity | The sustained activity index measures the highest number of steps sustained over a continuous 20 minute period. This was measured using a step activity monitor for 7 days at baseline and again at Week 24. Change from baseline scores were measured where a positive change from baseline indicates an improvement in the number of steps walked over 20 minutes of activity. | Baseline and Week 24 | 
| Change From Baseline in the Percentage of Time That Participants Spent Inactive | Change from baseline scores were measured where a negative change from baseline indicates less time spent inactive. | Baseline and Week 24 | 
| Change From Baseline in Time Taken for Participants to Ascend and Descend 4 Stairs | Participants were timed on their ability to climb up 4 stairs and timed separately to climb down 4 stairs at baseline and at week 24. The stairs were free-standing or the same flight of stairs was used at each assessment. Change from baseline scores were measured where a positive change from baseline indicates an improvement in the time taken for paticipants to ascend or descend 4 stairs. | Baseline and Week 24 | 
| Change From Baseline in Time Taken to Traverse 30 Feet | Participants were timed on their ability to travel 30 feet on the same surface at each assessment at baseline and at Week 24. Change from baseline scores were measured where a positive change from baseline indicates an improvement in the time taken to travel 30 feet. | Baseline and Week 24 | 
| Change From Baseline in Purdue Pegboard Test Scores | The Purdue Pegboard Test consists of a board with two sets of 25 holes, 4 concave cups, and a number of small metal pins. Participants were required to pick up the pins from a holder and place them in the holes as quickly as possible over 30 seconds with their dominant hand. The score was calculated as the number of pins placed into holes in 30 seconds and was measured at baseline and Week 24. Change from baseline scores were measured where a positive change from baseline indicates an improvement in the number of pins placed in the board. | Baseline and Week 24 | 
| Change From Baseline in Forced Vital Capacity (FVC) Volume While Sitting or Lying Down | FVC is the volume of air that can be forcibly exhaled from the lungs after taking the deepest breath possible, as measured by spirometry. | Baseline and Week 24 | 
| Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted While Sitting or Lying Down | FVC is the volume of air that can be forcibly exhaled from the lungs after taking the deepest breath possible, as measured by spirometry. | Baseline and Week 24 | 
| Change From Baseline in Manual Muscle Test (MMT) Scores | The MMT was used to assess muscle strength in the distal muscles and the proximal muscles. Distal muscles assessments included wrist extension, wrist flexion, ankle dorsiflexion and plantarflexion. Proximal muscle assessments included shoulder abduction, elbow extension, elbow flexion, hip extension, hip abduction, hip flexion, knee extension and knee flexion. In MMT, each muscle assessment was given a score of 0 to 5, where 0 indicated 'no contraction palpable' and 5 indicated 'normal strength'. The scores from each muscle were summed and the maximum overall score of all measured muscles was 140, the maximum distal score was 40 and the maximum proximal score was 80. Higher scores indicated higher muscle strength. Change from baseline scores were measured where a positive change from baseline indicates an improvement in muscle strength. | Baseline and Week 24 | 
| Change From Baseline in Selective Reminding Test T-Scores (Total Word and Delayed Words) | The Selective Reminding Test measures verbal learning and memory and involves remembering a verbal list of 12 words. Participants were required to recall the 12 words presented. Words that were missed on recall were presented again, and the process was repeated until all 12 words were correctly recalled. The total word list recall and delayed recall were calculated as T-scores. Raw scores were converted to T-score using available normative data. Change from baseline T-scores were measured where a positive change from baseline indicates improvement in performance. | Baseline and Week 24 | 
| Change From Baseline in Selective Reminding Test Raw Scores (Cued Recall and Recognition) | The Selective Reminding Test measures verbal learning and memory and involves remembering a verbal list of 12 words. Participants were required to recall the 12 words presented. Words that were missed on recall were presented again, and the process is repeated until all 12 words were correctly recalled. The cued recall scores ranged from 0-11 and multiple choice recognition scores ranged from 0-12. Change from baseline scores were measured where a positive change from baseline indicates an improvement in verbal recall and memory. | Baseline and Week 24 | 
| Change From Baseline in Rey Complex Figure (RCF) Test Scores | The Rey Complex Figure Test (RCFT) assesses visuospatial construction ability and visual memory through four different tests: copy (copying a complex geometric figure), immediate recall of the figure (drawing figure from memory at 3 minutes), delayed recall (drawing figure at 30 minutes after initial copy), and recognition score (selecting individual parts of the figure from sketches provided). Copy performances are divided into 18 components with a maximum score of 2 each. The maximum score for each figure is 36. | Baseline and Week 24 | 
| Change From Baseline in Letter-Number Sequencing (LNS) Test Scores | The LNS test from the Welchsler Adult Intelligence Scale-III was used to assess working memory. The test required that participants recall, in order, numbers and letters presented in an unordered sequence. The number of items is 21. With each item being marked 0 if reported incorrectly or 1 if reported correctly, the maximum score is 21. Raw scores were converted into T-scores using available normative data. Change from baseline T-scores were measured where a positive change from baseline indicates improvement in performance. | Baseline and Week 24 | 
| Change From Baseline in Trail Making Test (TMT) Scores | The TMT assesses executive function, sequencing, mental flexibility, visual spanning speed and motor function. In TMT Part A, the participant had to draw lines in the correct order between 25 numbers randomly arranged on the page. In TMT Part B, the participant had to draw lines between 25 numbers and letters in alternating order (e.g., 1-A-2-B...etc). Times for Part A and Part B were used to derive T-scores which can range from a minimum of 0 and a maximum of 100. Raw scores were converted into T-scores using available normative data. Change from baseline T-scores were measured where a positive change from baseline indicates improvement in performance. | Baseline and Week 24 | 
| Change From Baseline in the Stroop Color Word Test Scores | The Stroop Color Word Test measures selective attention and cognitive flexibility. The test has three parts, the Word test (reading words), the Color test (naming the ink color in which words are displayed) and the Color-Word test (saying the ink color not reading the word). An interference score was calculated from the Color, Word and Color-Word scores and is an indication of how well a person can complete a task while disregarding interfering information. Raw scores were converted into T-scores using available normative data. Scores range from 0 to 100. Change from baseline T-scores were measured where a positive change from baseline indicates improvement in performance. | Baseline and Week 24 | 
| Change From Baseline to Week 24 Scores on the Beck Depression Inventory II (BDI-II) Questionnaire | BDI-II is a validated self-reported instrument of 21 questions which are each scored 0-3. Total scores range from 0-63, with higher score totals indicating more severe depression symptoms. {0-9: indicates minimal depression; 0-18: indicates mild depression; 19-29: indicates moderate depression; 30-63: indicates severe depression. Lower scores indicate no or minimal depression, with a maximum total score of 63. | Baseline and Week 24 | 
| Change From Baseline in Average Fasting Glucose Concentration in the Blood | Participants were administered 75 grams (g) glucose solution prior to administration of the first dose of IPlex™ and after administration of the last dose. A 2-hour oral glucose tolerance test (OGTT) was performed under fasted conditions. | Baseline - Pre-dose and 30, 60, 90 and 120 minutes post glucose solution; Week 24 - Pre-dose and 30, 60, 90 and 120 minutes post glucose solution | 
| Change From Baseline in Average Fasting Insulin Concentration in the Blood | Participants were administered 75 g glucose solution prior to administration of the first dose of IPLEX™ and after administration of the last dose. A 2-hour OGTT was performed under fasted conditions. | Baseline - Pre-dose and 30, 60, 90 and 120 minutes post glucose solution; Week 24 - Pre-dose and 30, 60, 90 and 120 minutes post glucose solution | 
| Change From Baseline in Qualitative Insulin Sensitivity Check Index (QUICKI) | The QUICKI is based on fasting glucose and insulin measurements and are calculated using the following equation: QUICKI = 1/[ log(fasting glucose in mg/dL) + log (fasting insulin in uU/mL) ] | Baseline and Week 24 | 
| Change From Baseline in Insulin Sensitivity Index-Matsuda (ISI-Matsuda) | The ISI-Matsuda is based on the average glucose and insulin values obtained during the entire oral glucose tolerance test and are calculated using the following equation: ISI = 10,000 / √ [ fasting glucose (mg/dL) x fasting insulin(uU/mL) x mean glucose x mean insulin ] | Baseline and Week 24 | 
| Change From Baseline in Total Blood Cholesterol Level | A negative change from baseline indicates a decrease in total blood cholesterol level. | Baseline and Week 24 | 
| Change From Baseline in Total Blood Low-density Lipoproteins (LDL) Level | A positive change from baseline indicates an increase in total blood LDL level. | Baseline and Week 24 | 
| Change From Baseline in Total Blood High-density Lipoproteins (HDL) Level | A negative change from baseline indicates a decrease in total blood HDL level. | Baseline and Week 24 | 
| Change From Baseline in Total Blood Triglycerides Level | A negative change from baseline indicates a decrease in total blood triglycerides level. | Baseline and Week 24 | 
| Change From Baseline in Gastro-esophageal Reflux Disease (GERD) Symptom Frequency Questionnaire (GSFQ) Scores | The GSFQ contains 6 questions that assess the frequency of certain GERD symptoms and their impact on daily life. Scores were converted and reported out of 100 with higher scores indicative of more frequent and intense GERD symptoms. Change from baseline scores were measured where a negative change from baseline indicates less frequent and intense GERD symptoms. | Baseline and Week 24 | 
| Change From Baseline in Gastrointestinal Symptom Rating Scale for Irritable Bowel Syndrome (GSRS-IBS) Questionnaire Scores | The GSRS-IBS has 13 questions aimed at identifying the frequency and intensity of IBS symptoms during the past week. Answers are given a score from 1 (no discomfort at all) to 7 (very severe discomfort). A total score was calculated and ranged from 0 to 78. A lower score indicates less discomfort from IBS symptoms. Change from baseline scores were measured where a positive change from baseline indicates increased discomfort from IBS symptoms. | Baseline and Week 24 | 
| Change From Baseline in Swallowing Disturbance Questionnaire (SDQ) Scores | The SDQ had 15 questions relating to the oral phase and pharyngeal phase of swallowing. Answers for 14 questions were assigned a number (0-3) based on a 4-point verbal scale (never, seldom, frequently, very frequently) and the last question was a yes or no question about respiratory infections. A higher score is indicative of greater swallowing issues with 44.5 as the highest possible score. A total score of ≥ 11 suggests impairment. Change from baseline scores were measured where a positive change from baseline indicates increased swallowing impairment. | Baseline and Week 24 | 
| Change From Baseline in Short Form (36) (SF-36) Questionnaire Scores | The SF-36 is a 36-item questionnaire that evaluates quality of life through physical and mental health across eight scales, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability. Change from baseline scores were measured where a positive change from baseline indicates an improvement in quality of life. | Baseline and Week 24 | 
| Change From Baseline in Brief Pain Inventory (BPI) Questionnaire - Severity Scores | The BPI contains 15 questions that assess the severity of pain and its impact or interference on functions of daily life. Pain severity was measured as the mean of 7 items of the questionnaire on an 11-point scale where 0 indicates no pain and 10 indicates the worst pain. A higher score indicates greater pain. Categories assessed include worst pain in 24 hours and average pain. Change from baseline scores were measured where a positive change from baseline indicates a worsening in pain. | Baseline and Week 24 | 
| Change From Baseline in Brief Pain Inventory (BPI) Questionnaire - Interference Scores | The BPI contains 15 questions that assess the severity of pain and its impact or interference on functions of daily life. Pain interference is measured as the mean of 7 items on an 11-point scale where 0 indicates no interference and 10 indicates complete interference. A higher score indicates greater impairment due to pain. Change from baseline scores were measured where a positive change from baseline indicates a worsening of interference due to pain. | Baseline and Week 24 |