A Safety andTolerability Study of Multiple Doses of ISIS-DMPKRx in Adults With Myotonic Dystrophy Type 1

Sponsor

Ionis Pharmaceuticals, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT02312011

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will test the safety, tolerability, and pharmacokinetics of multiple escalating doses of ISIS-DMPKRx administered subcutaneously to adult patients with DM1.

Condition or Disease	Intervention/Treatment	Phase
Myotonic Dystrophy Type 1	Drug: IONIS-DMPKRx Drug: Placebo	Phase 1/Phase 2

Detailed Description

This is a Phase 1/2a multicenter, blinded, placebo-controlled study of ISIS-DMPK Rx in adult patients with DM1.

Study Design

Study Type:

Interventional

Actual Enrollment :

48 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2a Blinded, Placebo-Controlled Study to Assess the Safety, Tolerability, and Dose-range Finding of Multiple Ascending Doses of ISIS 598769 Administered Subcutaneously to Adult Patients With Myotonic Dystrophy Type 1

Study Start Date :

Dec 1, 2014

Actual Primary Completion Date :

Jul 1, 2016

Actual Study Completion Date :

Aug 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IONIS-DMPKRx IONIS DMPKRx is administered subcutaneously over the course of 6 weeks for dose levels 1, 2, 3, 4, and 5. IONIS DMPKRx is administered subcutaneously over the course of 12 weeks for dose levels 4 or 5.	Drug: IONIS-DMPKRx Drug Other Names: ISIS 598769
Placebo Comparator: Placebo A placebo is administered subcutaneously over the course of 6 weeks. A placebo is administered subcutaneously over the course of 12 weeks.	Drug: Placebo Placebo

Arm

Intervention/Treatment

Experimental: IONIS-DMPKRx

IONIS DMPKRx is administered subcutaneously over the course of 6 weeks for dose levels 1, 2, 3, 4, and 5. IONIS DMPKRx is administered subcutaneously over the course of 12 weeks for dose levels 4 or 5.

Drug: IONIS-DMPKRx

Drug

Other Names:

ISIS 598769

Placebo Comparator: Placebo

A placebo is administered subcutaneously over the course of 6 weeks. A placebo is administered subcutaneously over the course of 12 weeks.

Drug: Placebo

Placebo

Outcome Measures

Primary Outcome Measures

Safety (The number of participants with adverse events) [Participants will be followed for the duration of the study; an expected 24 - 32 weeks]
The number of participants with adverse events
Tolerability (The number of participants with adverse events) [Participants will be followed for the duration of the study; an expected 24 -32 weeks]
The number of participants with adverse events

Secondary Outcome Measures

Plasma Pharmacokinetics (Cmax, Tmax) [Plasma at 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hours after dosing.]
the maximal observed plasma drug concentration (Cmax) the time to reach Cmax (Tmax) the area under the plasma concentration time curve from the time of the subcutaneous dose to the last collected sample (24 hours after dosing)
Urine Pharmacokinetics (Amount of drug excreted in the urine) [0-24 hours post-dosing]
Amount of drug excreted in the urine

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements
Males or females aged 20 to 55 years old at the time of informed consent
Satisfy the following:
Females: non-pregnant and non-lactating, surgically sterile, post menopausal, abstinent, or if engaged in sexual relations of child-bearing potential, subject is using an acceptable contraceptive method from the time of signing the informed consent until at least 14 weeks after the last dose of Study Drug.
Males: surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, the subject must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 14 weeks after the last dose of Study Drug.
BMI <35.0 kg/m2
Genetic confirmation of DM1 with DMPK CTG repeat length ≥ 100
Onset of DM1 symptoms after the age of 12
Clinically apparent myotonia equivalent to hand opening time of at least 2 seconds, in the opinion of the Investigator
Ambulatory (orthoses allowed, canes and walkers not allowed) and able to walk at least 25 meters at screening

Exclusion Criteria:

Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome within 6 months of screening, major surgery within 3 months of screening) or physical examination
Clinically significant abnormalities in screening laboratory values that would render the subject unsuitable for inclusion
Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
Unwilling or unable to comply with study procedures (e.g., muscle biopsies), including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
Known history of or previous positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B
Active malignancy or history within last 5 years, except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix that has been successfully treated, or pilomatricoma
Treatment with another investigational drug, biologic agent, or device within one month of screening, or 5 half-lives of investigational agent, whichever is longer; any history of previous treatment with an oligonucleotide (including siRNA)
Recent history of or current drug or alcohol abuse
History of bleeding tendency or ongoing oral anticoagulation
Developmental delay, intellectual disability, or significant behavioral neuropsychiatric manifestations
Thyroid dysfunction that is untreated (if on thyroid hormone replacement therapy, need to have adequate and stable replacement over the previous 6 months)
Implanted device for the treatment of cardiac problems (i.e., pacemaker or defibrillator)
Clinically significant abnormal ECG or echocardiogram, or significant symptoms of cardiac dysfunction at Screening
Have a seizure disorder
If being treated with testosterone, on a stable replacement dose (i.e., for hypogonadism)
Treatment with corticosteroids within 8 weeks prior to the first dose of Study Drug
History of hypersensitivity to local anesthetics to be used in the biopsy procedure or components thereof
Treatment with anti-myotonia medication within 30 days prior to screening. May include, but not be limited to: Phenytoin, Carbamazepine, Procainamide, Disopyramide, Nifedipine, Acetazolamide, Clomipramine, Imipramine, Amytriptiline, Taurine, Quinine, Mexiletine
Have any condition, which, in the opinion of the investigator would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University Medical Center	Stanford	California	United States	94305
2	University of Florida	Gainesville	Florida	United States	32610
3	University of Kansas Medical Center	Kansas City	Kansas	United States	66103
4	Kennedy Krieger Institute	Baltimore	Maryland	United States	21205
5	University of Rochester	Rochester	New York	United States	14642
6	The Ohio State University	Columbus	Ohio	United States	43221
7	Houston Methodist	Houston	Texas	United States	77030
8	University of Utah	Salt Lake City	Utah	United States	84132