CDG1A, Pmm2-CDG
Conditions
Brief summary
Objective 1 (Primary): To determine the efficacy of acetazolamide in improving ataxia in patients with PMM2-CDG. Objective 2 (Secondary): To evaluate for any adverse events related to longer term acetazolamide administration. Objective 3 (Secondary): To examine the effect of acetazolamide on PMM2 biomarkers including carbohydrate deficient transferrin results, electrolytes (Na, K, Cl, CO2), VBG (pH, pCO2, PO2, CO2, Base excess), liver function tests (AST, ALT, GGT, indirect and direct bilirubin, total protein, albumin, alkaline phosphatase), kidney function tests (BUN, Creatinine, Urinalysis, urine calcium/creatinine ratio, urine protein/creatinine ratio), growth (height, weight, head circumference), vital signs (blood pressure, respiratory rate, heart rate), PROMIS scores, dysarthria using the PATA score, and NPCRS score. Objective 4 (Secondary): To explore characteristics of individuals with PMM2-CDG who do not respond to acetazolamide.
Detailed description
This study is double-blind, placebo-controlled, 1:1 randomized clinical therapeutic trial of acetazolamide for the treatment of ataxia in patients with PMM2-CDG. Clinical history and screening data will be reviewed to determine subject eligibility. Potential subjects who have a molecularly and/or biochemical confirmed diagnosis of PMM2-CDG will be consented. Baseline data will be collected prior to randomization and at treatment initiation. Subjects who meet all inclusion criteria and none of the exclusion criteria will be enrolled into the study. Each subject who meets all the inclusion and none of the exclusion criteria will then be randomized to placebo or acetazolamide. They will be administered weight-dependent doses of acetazolamide or an equivalent volume of placebo twice daily by mouth. Initial dose of acetazolamide is 8 mg/kg/day if subjects are taking the liquid formulation, or as per Table 1b if they are taking the capsule formulation. If taking the liquid formulation, the dose of study drug will be increased by 7 mg/kg/day to a maximum of 22 mg/kg/day (not to exceed 1000 mg/day) if well tolerated with no treatment related SAEs or abnormal pH. If the pH is \<7.32, the dose will be reduced by 7 mg/kg/day. The dose will be adjusted similarly according to Table 1b if taking the capsule formulation. Subjects will be randomized after Visit 1, will initiate blinded therapy within the first week, and will continue on prescribed/adjusted blinded treatment until Visit 4. Of note, the concentration of the liquid formulation and the amount of milligrams of acetazolamide per capsule will stay constant, and the volume or number of capsules will be adjusted based on tolerance as assessed by symptoms and laboratories. If an individual is randomized to the placebo arm, the initial volume will be equivalent to 7 mg/kg/day or the initial number of capsules as per Table 1, and volume or number of capsules will also be adjusted based on symptoms and laboratory values each time dose adjustment is planned. Open label period will then begin after Visit 4 up to Visit 9 (see Figure 1 and Table 3). As both the subject and investigator do not know if the subject received placebo or acetazolamide, the dose of acetazolamide will be started at Visit 4 at 8 mg/kg/day and titrated upwards in the same manner in Visits 5 and 6 (remote) as in Visits 2 and 3 (remote). Subjects will have the option to withdraw from the study any time after Visit 4 if they do not wish to proceed onto or continue with the open label phase.
Interventions
DRUGPlacebo
administered orally or enterally
DRUGAcetazolamide
administered orally or enterally
Sponsors
Seattle Children's Hospital
Children's Hospital of Philadelphia
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind
Intervention model description
Randomized, double blind, placebo controlled, with optional extension period
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Molecularly and/or enzymatically-confirmed PMM2-CDG, * Age ≥4 years old, and * Affected with ataxia evidenced by mini International Cooperative Ataxia Rating Scale (Mini-ICARS) score \>0 at baseline.
Exclusion criteria
* Hepatic impairment defined as AST/ALT \>5x ULN in the last 12 months * Renal impairment defined as serum creatinine: \> 0.5 mg/dL (\<6 years); \> 0.7 mg/dL (7-10 years); \> 1.24 mg/dL (\> 11 years)- Hypersensitivity to acetazolamide * Hypersensitivity to any of the components of the placebo * History of treatment with experimental drug within 28 days of Visit 1 * Currently taking Mecamylamine, Sodium Phosphates, Salicylates, Mefloquine, Methenamine and other Carbonic Anhydrase Inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Acetazolamide on Ataxia Measured Via Miniature International Cooperative Ataxia Rating Scale (Mini-ICARS) | baseline-6 months | To achieve this goal, we compared the change of Mini-ICARS score from baseline to after six months of treatment between the placebo and active treatment groups. Minimal score is 0, maximum score is 100, higher score indicates greater impairment. Each subscale has an ordinal scale with a 0 indicating normal and the higher score indicating greater impairment or that the patient was unable to complete the task. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Electrolyte Balance Testing | through study completion, approximately 2 years | Electrolyte balance was assessed through combination testing on concentration of potassium, sodium, chloride, bicarbonate, magnesium, calcium, and phosphate. The number of participants who experience a drug related adverse event related to abnormal electrolyte balance. |
| Urine Calcium Excretion Testing | through study completion, approximately 2 years | Urine calcium excretion is measured by mg excreted per day. The number of participants who experience a drug related adverse event related to abnormal excretion of calcium. |
| Examine Effect of Acetazolamide on PMM2 Biomarker Carbohydrate Deficient Transferrin | 6 months | Number of patients with abnormal ratio result will be recorded to understand the effect acetazolamide has on this biomarker |
| Abnormal Blood pH Value | through study completion, approximately 2 years | Blood pH level was assessed through venous blood gas test. The number of participants who experience a drug related adverse event related to abnormal blood pH value. |
| Change in Dysarthria as Measured by the PATA Score | baseline, 6 months | PATA test measures the number of times a patient can say the word PATA in a 10 second time period. Number of PATAs spoken in 10 seconds indicates level of dysarthria. The higher the score the less dysarthria, the lower the score more dysarthria. |
| Change in Nijmegen Pediatric CDG Rating Scale (NPCRS) | baseline, 6 months | The NPCRS is a scale that evaluates the patient's current function, system specific involvement, and current clinical assessment. Total scores range from 0 - 82. A mild score is 0-14, moderate score is 15-25, and severe is a score \>26. |
| Change in Patient Reported Outcomes Measurement Information System (PROMIS) Score | baseline, 6 months | PROMIS = Physical activity 10-items from 1(no days) to 5(6-7 days), Strength impact 12-item from 1(no days) to 5(6-7 days), Fatigue 23-item from 1(never) to 5(almost always), Mobility 23-item from 1(not able to do) to 5(with no trouble), Pain interference 13-item from 1(never) to 5(almost always), Upper extremity coordination 29-item from 1(not able to do) to 5(with no trouble), Global Health 9-item from 1(poor) to 5( excellent), Parent Proxy Mobility 8-item from 1(not able to do) to 5(with no trouble), Anxiety 8-item from 1(never) to 5(almost always), Depresson 8-item from 1(never) to 5(almost always), Parent Proxy Fatigue 8-item from 1(never) to 5(almost always), Peer relationships 8-item from 1(never) to 5(almost always), Parent proxy pain interference 8-item from 1(never) to 5(almost always), Pain intensity 1-item from 0(no pain) to 10(worst pain). Total scores range from 168 - 845. Lower scores indicate worse health, higher scores indicate better health |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Acetazolamide Acetazolamide was administered via capsule or liquid suspension. Capsule was 250 mg oral capsules encapsulated by gelatin capsule and filled with lactose to match placebo. Liquid suspension was 25 mg/mL oral suspension but adding 125 mg Acetazolamide tablets to suspending agent Ora-blend
Acetazolamide: administered orally or enterally | 13 |
| Placebo Placebo was administered via capsule or liquid suspension. Capsule was a gelatin capsule filled with lactose powder to match Acetazolamide. Liquid suspension was a Ora-blend.
Placebo: administered orally or enterally | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Physician Decision | 3 | 5 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 7 |
Baseline characteristics
| Characteristic | Acetazolamide | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 13.62 years STANDARD_DEVIATION 8.47 | 12.30 years STANDARD_DEVIATION 7.11 | 10.88 years STANDARD_DEVIATION 5.26 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 22 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 21 Participants | 11 Participants |
| Region of Enrollment United States | 13 participants | 25 participants | 12 participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 2 Participants |
| Sex: Female, Male Male | 8 Participants | 18 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 12 |
| other Total, other adverse events | 9 / 13 | 8 / 12 |
| serious Total, serious adverse events | 1 / 13 | 3 / 12 |
Outcome results
Primary
Efficacy of Acetazolamide on Ataxia Measured Via Miniature International Cooperative Ataxia Rating Scale (Mini-ICARS)
To achieve this goal, we compared the change of Mini-ICARS score from baseline to after six months of treatment between the placebo and active treatment groups. Minimal score is 0, maximum score is 100, higher score indicates greater impairment. Each subscale has an ordinal scale with a 0 indicating normal and the higher score indicating greater impairment or that the patient was unable to complete the task.
Time frame: baseline-6 months
Population: Data was not collected nor analyzed for two subjects in the Acetazolamide arm and one subject in the Placebo arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetazolamide | Efficacy of Acetazolamide on Ataxia Measured Via Miniature International Cooperative Ataxia Rating Scale (Mini-ICARS) | 1.64 score on a scale | Standard Deviation 3.2 |
| Placebo | Efficacy of Acetazolamide on Ataxia Measured Via Miniature International Cooperative Ataxia Rating Scale (Mini-ICARS) | 1.36 score on a scale | Standard Deviation 3.23 |
p-value: 0.84t-test, 2 sided
Secondary
Abnormal Blood pH Value
Blood pH level was assessed through venous blood gas test. The number of participants who experience a drug related adverse event related to abnormal blood pH value.
Time frame: through study completion, approximately 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Acetazolamide | Abnormal Blood pH Value | 0 Participants |
| Placebo | Abnormal Blood pH Value | 1 Participants |
p-value: 0.48Fisher Exact
Secondary
Change in Dysarthria as Measured by the PATA Score
PATA test measures the number of times a patient can say the word PATA in a 10 second time period. Number of PATAs spoken in 10 seconds indicates level of dysarthria. The higher the score the less dysarthria, the lower the score more dysarthria.
Time frame: baseline, 6 months
Population: Data was not collected nor analyzed for four participants in the Acetazolamide arm and three participants in the Placebo arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetazolamide | Change in Dysarthria as Measured by the PATA Score | 2.30 words/10 sec | Standard Deviation 3.71 |
| Placebo | Change in Dysarthria as Measured by the PATA Score | 0.59 words/10 sec | Standard Deviation 3.11 |
p-value: 0.31t-test, 2 sided
Secondary
Change in Nijmegen Pediatric CDG Rating Scale (NPCRS)
The NPCRS is a scale that evaluates the patient's current function, system specific involvement, and current clinical assessment. Total scores range from 0 - 82. A mild score is 0-14, moderate score is 15-25, and severe is a score \>26.
Time frame: baseline, 6 months
Population: Data was not collected nor analyzed for three participants in the Acetazolamide arm and one participant in the Placebo arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetazolamide | Change in Nijmegen Pediatric CDG Rating Scale (NPCRS) | 1.20 score on a scale | Standard Deviation 1.99 |
| Placebo | Change in Nijmegen Pediatric CDG Rating Scale (NPCRS) | 0.27 score on a scale | Standard Deviation 1.79 |
p-value: 0.09t-test, 2 sided
Secondary
Change in Patient Reported Outcomes Measurement Information System (PROMIS) Score
PROMIS = Physical activity 10-items from 1(no days) to 5(6-7 days), Strength impact 12-item from 1(no days) to 5(6-7 days), Fatigue 23-item from 1(never) to 5(almost always), Mobility 23-item from 1(not able to do) to 5(with no trouble), Pain interference 13-item from 1(never) to 5(almost always), Upper extremity coordination 29-item from 1(not able to do) to 5(with no trouble), Global Health 9-item from 1(poor) to 5( excellent), Parent Proxy Mobility 8-item from 1(not able to do) to 5(with no trouble), Anxiety 8-item from 1(never) to 5(almost always), Depresson 8-item from 1(never) to 5(almost always), Parent Proxy Fatigue 8-item from 1(never) to 5(almost always), Peer relationships 8-item from 1(never) to 5(almost always), Parent proxy pain interference 8-item from 1(never) to 5(almost always), Pain intensity 1-item from 0(no pain) to 10(worst pain). Total scores range from 168 - 845. Lower scores indicate worse health, higher scores indicate better health
Time frame: baseline, 6 months
Population: Data was not collected nor analyzed for seven subjects in the Acetazolamide arm and four subjects in the Placebo arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetazolamide | Change in Patient Reported Outcomes Measurement Information System (PROMIS) Score | 3.02 score on a scale | Standard Deviation 4.45 |
| Placebo | Change in Patient Reported Outcomes Measurement Information System (PROMIS) Score | 0.75 score on a scale | Standard Deviation 4.09 |
Secondary
Electrolyte Balance Testing
Electrolyte balance was assessed through combination testing on concentration of potassium, sodium, chloride, bicarbonate, magnesium, calcium, and phosphate. The number of participants who experience a drug related adverse event related to abnormal electrolyte balance.
Time frame: through study completion, approximately 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Acetazolamide | Electrolyte Balance Testing | 0 Participants |
| Placebo | Electrolyte Balance Testing | 1 Participants |
p-value: 0.48Fisher Exact
Secondary
Examine Effect of Acetazolamide on PMM2 Biomarker Carbohydrate Deficient Transferrin
Number of patients with abnormal ratio result will be recorded to understand the effect acetazolamide has on this biomarker
Time frame: 6 months
Population: Data was not collected nor analyzed for this outcome measure. Data collection for this outcome never occurred. PMM2 biomarker carbohydrate deficient transferrin was not collected for any subjects. The test was never collected for any subjects.
Secondary
Urine Calcium Excretion Testing
Urine calcium excretion is measured by mg excreted per day. The number of participants who experience a drug related adverse event related to abnormal excretion of calcium.
Time frame: through study completion, approximately 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Acetazolamide | Urine Calcium Excretion Testing | 0 Participants |
| Placebo | Urine Calcium Excretion Testing | 0 Participants |
p-value: >0.99Fisher Exact