Huntington Disease
Conditions
Keywords
Study of Minocycline in Huntington's Disease
Brief summary
This study is being conducted to assess the impact of minocycline on the progression of symptoms of HD. The study will also assess whether it is reasonable to continue with further study of minocycline in HD. We will measure the effect of minocycline on HD by measuring the change in Huntington's disease symptoms.
Detailed description
The DOMINO study is a randomized, double-blind, multi-center, futility study of minocycline in patients with HD. Subjects will be randomized (3:1) to one of the two study arms: (1) the group that receives active minocycline (100 mg po b.i.d.), and (2) the group that receives placebo. Subjects will be enrolled over an approximate six-month period and remain on blinded study drug for 18 months. The primary analysis will involve a comparison of the change over time in TFC between the minocycline group and a fixed value determined from historical control data. A placebo group will also be included to facilitate blinding and to permit a descriptive assessment of the validity of the assumed change over time in historical controls.
Interventions
DRUGminocycline
Minocycline: Oral; minocycline 100 mg capsules administered twice a day with the morning and evening meal (\ 8 hours apart)
DRUGMatching placebo
Matching placebo 1 capsule twice daily, 18 months treatment duration.
Sponsors
FDA Office of Orphan Products Development
Merit Cudkowicz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years or older * Clinical features of HD and a confirmatory family history of HD; and/or genetically confirmed HD * Independently walking and fully self-sufficient in activities of daily living (eating, dressing, bathing) * Able to take medication (capsules) by mouth
Exclusion criteria
* History of known hypersensitivity or intolerability to minocycline or known allergy to any tetracycline * History of vestibular disease * Subjects with underlying hematologic, hepatic or renal disease * History of systemic lupus erythematosus (SLE)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 18 in the Total Functional Capacity (TFC) Scale [LOCF Imputation Method] | Baseline to 18 months | Establish preliminary estimate of minocycline's impact on progression of HD (measured by the change in Total Functional Capacity (TFC) score of Unified Huntington's Disease Rating Scale \[UHDRS\] between baseline & Month 18), and to assess futility of further study of minocycline. TFC consists of five ordinally scaled items assessing a person's capacity with: 1. occupation 2. financial affairs 3. domestic responsibilities 4. activities of daily living and 5. independent living. Total score ranges from zero (worst) to 13 (best). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 18 in the Total Functional Capacity (TFC) Scale [Regression Based Multiple Imputation Method] | Baseline to 18 months | TFC consists of five ordinally scaled items assessing a person's capacity with: (1) occupation; (2) financial affairs; (3) domestic responsibilities; (4) activities of daily living; and (5) independent living. Total score ranges from zero (worst) to 13 (best). Regression based imputation was used to impute missing values. |
Countries
Canada, United States
Participant flow
Recruitment details
Between April 2006 and June 2007 , 134 patients were screened and 114 subjects were randomized at 12 Huntington Study Group clinical sites.
Pre-assignment details
20 subjects were excluded from group assignment after screening: 14 failed inclusion criteria and 6 withdrew consent. Minocycline 90 days prior to baseline and open-label during trial not permitted. Other tetracyclines, investigational drugs, lithium, digoxin, methoflurane anesthesia, theophylline and lupus-symptom causing drugs not permitted.
Participants by arm
| Arm | Count |
|---|---|
| Minocycline 100 mg Twice Daily Minocycline 100 mg/twice daily (minocycline to placebo 3:1 ratio randomization). | 87 |
| Matching Placebo Twice Daily Matching placebo twice daily (minocycline to placebo 3:1 ratio randomization. | 27 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 0 |
| Overall Study | Death | 3 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Minocycline 100 mg Twice Daily | Matching Placebo Twice Daily | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 85 Participants | 25 Participants | 110 Participants |
| Age Continuous | 47.1 years STANDARD_DEVIATION 10.3 | 47.8 years STANDARD_DEVIATION 10.6 | 47.3 years STANDARD_DEVIATION 10.4 |
| Region of Enrollment Canada | 7 participants | 2 participants | 9 participants |
| Region of Enrollment United States | 80 participants | 25 participants | 105 participants |
| Sex: Female, Male Female | 46 Participants | 15 Participants | 61 Participants |
| Sex: Female, Male Male | 41 Participants | 12 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 74 / 87 | 23 / 27 |
| serious Total, serious adverse events | 11 / 87 | 1 / 27 |
Outcome results
Primary
Change From Baseline to Month 18 in the Total Functional Capacity (TFC) Scale [LOCF Imputation Method]
Establish preliminary estimate of minocycline's impact on progression of HD (measured by the change in Total Functional Capacity (TFC) score of Unified Huntington's Disease Rating Scale \[UHDRS\] between baseline & Month 18), and to assess futility of further study of minocycline. TFC consists of five ordinally scaled items assessing a person's capacity with: 1. occupation 2. financial affairs 3. domestic responsibilities 4. activities of daily living and 5. independent living. Total score ranges from zero (worst) to 13 (best).
Time frame: Baseline to 18 months
Population: The primary analyses were performed according to the intent to treat principle and included all randomized subjects. Two strategies were used to address missing data: 1. Last observation carried forward (LOCF) was used to impute missing values and 2. A secondary method of regression-based multiple imputation was also used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Minocycline 100 mg Twice Daily | Change From Baseline to Month 18 in the Total Functional Capacity (TFC) Scale [LOCF Imputation Method] | 1.55 units on a scale | Standard Deviation 1.85 |
| Matching Placebo Twice Daily | Change From Baseline to Month 18 in the Total Functional Capacity (TFC) Scale [LOCF Imputation Method] | 1.15 units on a scale | Standard Deviation 1.7 |
Secondary
Change From Baseline to Month 18 in the Total Functional Capacity (TFC) Scale [Regression Based Multiple Imputation Method]
TFC consists of five ordinally scaled items assessing a person's capacity with: (1) occupation; (2) financial affairs; (3) domestic responsibilities; (4) activities of daily living; and (5) independent living. Total score ranges from zero (worst) to 13 (best). Regression based imputation was used to impute missing values.
Time frame: Baseline to 18 months
Population: The primary analyses were performed according to the intent to treat principle and included all randomized subjects. Two strategies were used to address missing data: 1. Last observation carried forward (LOCF) was used to impute missing values and 2. A secondary method of regression-based multiple imputation was also used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Minocycline 100 mg Twice Daily | Change From Baseline to Month 18 in the Total Functional Capacity (TFC) Scale [Regression Based Multiple Imputation Method] | 1.71 units on a scale | Standard Deviation 1.96 |
| Matching Placebo Twice Daily | Change From Baseline to Month 18 in the Total Functional Capacity (TFC) Scale [Regression Based Multiple Imputation Method] | 1.15 units on a scale | Standard Deviation 1.7 |