Conditions: Pmm2-CDG CDG1A
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

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.

Arms:
arm 1: Acetazolamide administered via capsule or liquid suspension. Capsule would be 250 mg oral capsules encapsulated by gelatin capsule and filled with lactose to match placebo. Liquid suspension would be 25 mg/mL oral suspension but adding 125 mg Acetazolamide tablets to suspending agent Ora-blend arm 2: Placebo administered via capsule or liquid suspension. Capsule would be a gelatin capsule filled with lactose powder to match Acetazolamide. Liquid suspension would be Ora-blend.

Interventions: intervention 1: Placebo intervention 2: Acetazolamide
Intervention descriptions: intervention 1: administered orally or enterally intervention 2: administered orally or enterally

Protocol document:
Prot_SAP_000.pdf: 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY EVALUATING 
ACETAZOLAMIDE EFFICACY IN 
ATAXIA IN PMM2-CDG 
 
NCT04679389   
 
1/26/2024 


Acetazolamide Trial 
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Revised 01/26/2024 
 
 
Page 1 of 50 
Investigator: Dr. Marc C. Patterson CONFIDENTIAL 
 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED  
STUDY EVALUATING ACETAZOLAMIDE EFFICACY IN 
ATAXIA IN PMM2-CDG 
 
 
Regulatory Sponsor: 
 
Department of Clinical Genomics, Mayo Clinic 
200 First St SW, Rochester, MN 55901 
 
Study Product: 
Acetazolamide 
Protocol Number: (IRBe) 
20-000634 
 
 
 
 
 
 
 
 
Initial version: 11/03/2020 Version (1.0)  
Revised: 05/06/2021; Version 3.0 
Revised: 06/30/2021; Version 4.0 
 
Revised: 10/19/2022; Version 5.0 
Revised: 11/09/2022, Version 6.0 
Revised: 11/18/2022, Version 7.0 
Revised: 12/20/2022, Version 8.0 
 
 
 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 5 
1 
INTRODUCTION ................................................................................................................................. 7 
1.1 
BACKGROUND .................................................................................................................................... 7 
1.2 
INVESTIGATIONAL AGENT .................................................................................................................... 7 
1.3 
CLINICAL DATA TO DATE..................................................................................................................... 9 
1.4 
DOSE RATIONALE.............................................................................................................................. 10 
1.5 
RISKS AND BENEFITS ......................................................................................................................... 14 
2 
STUDY OBJECTIVES ........................................................................................................................ 15 
3 
STUDY DESIGN ................................................................................................................................. 16 
3.1 
GENERAL DESCRIPTION ..................................................................................................................... 16 
3.2 
NUMBER OF SUBJECTS ....................................................................................................................... 16 
3.3 
DURATION OF PARTICIPATION ............................................................................................................ 17 
3.4 
PRIMARY STUDY ENDPOINTS .............................................................................................................. 17 
3.5 
SECONDARY STUDY ENDPOINTS ......................................................................................................... 17 
3.6 
PRIMARY SAFETY ENDPOINTS ............................................................................................................ 17 
3.7 
IDENTIFICATION OF SOURCE DATA ...................................................................................................... 18 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ...................................................... 19 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 19 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 19 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ....................................................................... 20 
4.4 
SUBJECT WITHDRAWAL CRITERIA ...................................................................................................... 20 
5 
STUDY DRUG .................................................................................................................................... 20 
5.1 
DESCRIPTION .................................................................................................................................... 20 
5.2 
TREATMENT REGIMEN ....................................................................................................................... 21 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ................................................................ 22 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................................... 22 
5.5 
SUBJECT COMPLIANCE MONITORING ................................................................................................... 23 
5.6 
PRIOR AND CONCOMITANT THERAPY .................................................................................................. 23 
5.7 
PACKAGING ...................................................................................................................................... 23 
5.8 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................. 24 
5.8.1 
Receipt of Drug Supplies .......................................................................................................... 24 
5.8.2 
Storage ................................................................................................................................... 24 
5.8.3 
Dispensing of Study Drug ......................................................................................................... 24 
5.8.4 
Return or Destruction of Study Drug ......................................................................................... 24 
6 
STUDY PROCEDURES ...................................................................................................................... 25 
6.1 
VISIT 1 – WEEK 0 .............................................................................................................................. 25 
6.2 
VISIT 2 (REMOTE)– WEEK 2-3 ............................................................................................................ 26 
6.3 
VISIT 3 (REMOTE)– WEEK 3-5 ............................................................................................................ 27 
6.4 
VISIT 4 (REMOTE)– VISIT 3 +1-3 WEEKS .............................................................................................. 27 
6.5 
VISIT 5 – WEEK 21-34 ....................................................................................................................... 27 
6.6 
VISIT 6 (REMOTE)– VISIT 5 +1-3 WEEKS .............................................................................................. 28 
6.7 
VISIT 7 (REMOTE)– VISIT 6 + 1-3 WEEKS ............................................................................................. 28 
6.8 
VISIT 8 (REMOTE)– VISIT 7 +1-3 WEEKS .............................................................................................. 28 
6.9 
VISIT 9 – WEEK 49-105 ...................................................................................................................... 29 


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6.10 VISIT – EARLY TERMINATION ............................................................................................................. 29 
7 
STATISTICAL PLAN ......................................................................................................................... 33 
7.1 
SAMPLE SIZE DETERMINATION ........................................................................................................... 33 
7.2 
STATISTICAL METHODS ..................................................................................................................... 33 
7.3 
SUBJECT POPULATIONS FOR ANALYSIS ................................................................................................ 35 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 35 
8.1 
DEFINITIONS ..................................................................................................................................... 36 
8.2 
RECORDING OF ADVERSE EVENTS ....................................................................................................... 38 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .......................................... 39 
8.3.1 
Investigator reporting: notifying the IRB .................................................................................... 39 
8.3.2 
Investigator reporting: Notifying the FDA .................................................................................. 40 
8.4 
UNMASKING/UNBLINDING PROCEDURES ............................................................................................. 40 
8.5 
STOPPING RULES ............................................................................................................................... 41 
8.6 
MEDICAL MONITORING ..................................................................................................................... 41 
8.6.1 
Independent Data and Safety Monitoring Board ......................................................................... 41 
9 
DATA HANDLING AND RECORD KEEPING .................................................................................. 42 
9.1 
CONFIDENTIALITY ............................................................................................................................. 42 
9.2 
SOURCE DOCUMENTS ........................................................................................................................ 42 
9.3 
CASE REPORT FORMS ........................................................................................................................ 42 
9.4 
RECORDS RETENTION ........................................................................................................................ 44 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 44 
10.1 STUDY MONITORING PLAN ................................................................................................................. 44 
10.1.1 
Study synopsis ......................................................................................................................... 45 
10.1.2 
Roles and Responsibilities ........................................................................................................ 45 
10.1.3 
Trial Safety .............................................................................................................................. 45 
10.1.4 
Reportable Events .................................................................................................................... 45 
10.1.5 
Data Management, Analysis, and Quality Assurance................................................................... 45 
10.2 AUDITING AND INSPECTING ................................................................................................................ 46 
11 
ETHICAL CONSIDERATIONS ......................................................................................................... 46 
12 
STUDY FINANCES ............................................................................................................................ 48 
12.1 FUNDING SOURCE ............................................................................................................................. 48 
12.2 CONFLICT OF INTEREST ...................................................................................................................... 48 
13 
PUBLICATION PLAN ....................................................................................................................... 48 
14 
REFERENCES ................................................................................................................................... 48 
15 
ATTACHMENTS ............................................................................................................................... 50 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine Transaminase 
AST 
Aspartate Aminotransferase 
BSAP 
Bone-specific alkaline phosphatase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CDG 
Congenital Disorder of Glycosylation 
CFR 
Code of Federal Regulations 
Cl 
Chloride 
CNS 
Central Nervous System 
CO2 
Carbon Dioxide 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
Carboxy-terminal collagen crosslinks 
DSMB 
Data and Safety Monitoring Board 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
ICARS 
The International Cooperative Ataxia Rating Scale 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
K 
Potassium 
LFT 
Liver Function Tests 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MVRD 
Midsagittal Vermis Relative Diameter  
Na 
Sodium 
NPCRS 
Nijmegen Pediatric CDG Rating Scale 
PTH 
Parathyroid Hormone 
pCO2 
Partial Pressure of Carbon Dioxide 
PHI 
Protected Health Information 
PI 
Principal Investigator 
Plt 
Platelet 
PMM2 
Phosphomannomutase deficiency 
pO2 
Partial Pressure of Oxygen 
PRO 
Patient Reported Outcome 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
VBG 
Venous Blood Gas  


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WBC 
White Blood Cell Count 
% 
Percent 
 
Study Summary 
Title 
A randomized, double-blind, placebo-controlled study evaluating 
Acetazolamide efficacy in ataxia in PMM2-CDG   
Running Title 
Acetazolamide Trial in PMM2-CDG 
Protocol Number 
20-000634 
Methodology 
Randomized, double-blind, placebo-controlled, parallel 
Overall Study 
Duration 
1 years (52 weeks) 
Subject Participation 
Duration 
Treatment period = 6 months (26 weeks); Open Label period = 6 
additional months (26 weeks); Total of 1 year (52 weeks) 
Single or Multi-Site  
Multicenter – 3 sites (Seattle Children’s Hospital, Children’s Hospital 
of Philadelphia, Mayo Clinic) 
Objectives 
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) or bicarbonate/CO2, 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. 
Number of Subjects 
26 total subjects 


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Diagnosis and Main 
Inclusion/Exclusion 
Criteria 
Inclusion criteria:  
1. Biallelic pathogenic or likely pathogenic variants in PMM2 
OR 
Biallelic variants of uncertain significance, pathogenic, or likely 
pathogenic variants in PMM2  AND  Enzymatic confirmation of PMM2 
enzyme deficiency 
2. Age ≥4 years old, and  
3. Affected with ataxia evidenced by mini International Cooperative Ataxia 
Rating Scale (Mini-ICARS) score >0 at baseline.  
 
Exclusion criteria:  
1. Hepatic impairment defined as AST/ALT >3.0 - 5.0 x ULN if baseline 
was normal; >3.0 - 5.0 x baseline if baseline was abnormal 
2. Renal impairment defined as serum creatinine1.5-1.9 times ULN for age 
OR ≥ 26.5 umol/l increase from ULN for age 
3. Hypokalemia 
4. Hyponatremia 
5. Hyperchloremic acidosis 
6. Adrenal insufficiency  
7. Hypersensitivity to acetazolamide 
8. Hypersensitivity to any of the components of the placebo 
9. History of treatment with experimental drug within 28 days of Visit 1 
10. Currently taking Mecamylamine, Sodium Phosphates, Salicylates, 
Mefloquine, Methenamine and other Carbonic Anhydrase Inhibitors 
11. Weight <10 kg 
Study Product, Dose, 
Route, Regimen 
Acetazolamide or Placebo 
Acetazolamide capsules ≤30 mg/kg/day divided BID or matching 
placebo, divided BID daily, by mouth. 
Due to the potential of subject intolerance, we will start patients on a 
lower dose divided BID and titrate up in a stepwise manner per table 1 
if well tolerated with no AEs or abnormal pH. If the pH is <7.3 and/or 
bicarbonate <21, the dose will be reduced by 7mg/kg/day. 
Duration of 
Administration 
12 months (52 weeks) total, 6 months (26 weeks) blinded, 6 months 
(26 weeks) open label extension 
Reference therapy 
Placebo 
Statistical 
Methodology 
The primary analysis will be conducted using the full analysis set, 
defined as all randomized patients who complete the baseline and 6-
month visits. The between-arm mean difference in the change in Mini-
ICARS score from baseline to 6 months will be evaluated via a two-
sample t-test. The primary analysis will include all patients with a 
baseline and 6-month Mini-ICARS score. 
 
 
 
 


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1 Introduction 
 
This document is a protocol for a human research study. This study will be carried out as 
described in this protocol and comply with all principles of Good Clinical Practice (GCP), as 
described in the United States Code of Federal Regulation (CFR) 21 Parts 11, 50, 54, 56, and 
312 and the appropriate International Conference on Harmonization guidance documents.  
1.1 
Background 
 
Phosphomannomutase deficiency, also known as PMM2-CDG, is the most common congenital 
disorder of glycosylation (CDG), with over 700 reported cases worldwide. It is an autosomal 
recessive disorder caused by biallelic pathogenic variants in the PMM2 gene (Grunewald et al. 
2002, Jaeken et al. 1980, 2014). Clinically, PMM2-CDG is characterized by multisystemic 
severe disease and cerebellar atrophy in infancy, neurologic disease including ataxia and 
developmental delay in childhood, and/or stable intellectual disability in adulthood (Freeze et al. 
2012, Grunewald et al. 2009).  
 
Cerebellar atrophy and cerebellar motor symptoms are common in patients with PMM2-CDG, 
typically more severe in the first decade of life (Barone et al. 2014, 2015, DeDiego et al. 2017). 
On a quality of life questionnaire administered to all families attending the 2019 World CDG 
conference, ataxia was identified as a major symptom impacting daily life in all age groups 
(unpublished data). Cerebellar dysfunction is a major cause of long-term disability, loss of 
autonomy, and limitations in daily life for patients with PMM2-CDG.  
 
The International Cooperative Ataxia Rating Scale (ICARS) is a scoring system that has been 
validated to assess the severity of ataxia symptoms in children and adults with PMM2-CDG. 
(Serrano et al. 2015, 2017). The ICARS assessment was validated against cerebellar atrophy as 
calculated by the midsagittal vermis relative diameter (MVRD) on MRI (i.e., using a midsagittal 
section and measuring total posterior cranial fossa diameter in a linear segment from the 
posterior commissura to the opisthium and the largest sagittal diameter of the cerebellum parallel 
to the previous linear segment. The ratio of the cerebellum diameter over the total posterior 
cranial fossa diameter was used (Serrano et al. 2015)). ICARS showed significant negative 
correlation with MVRD (rs −0.87, p = 0.003).  
 
Ataxia symptoms and stroke like episodes in CACNA1A-related disorder, a genetic 
channelopathy, are attributable to gain-of-function effects on channel gating in the Cav2.1 
channel. Deficient N-glycosylation of Cav2.1 induce a similar gain-of-function effect on this 
channel (Izquierdo-Serra et al. 2018). Lowering of intracellular pH and thus transmembrane 
potential may decrease the activation of Cav2.1. This, in turn, may restore the excitability and 
resting activity of neurons. Thus lowering the intracellular pH may ameliorate the cerebellar 
symptoms of PMM2-CDG, given the hypothesis that cerebellar symptoms are partially due to 
dysfunctional hypo glycosylated channels such as Cav2.1.  
1.2 
Investigational Agent 
 


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Acetazolamide  
 
Acetazolamide is a potent carbonic anhydrase inhibitor, effective in the control of fluid secretion, 
in the treatment of certain convulsive disorders, and in the promotion of diuresis in instances of 
abnormal fluid retention. Acetazolamide is not a mercurial diuretic. Rather, it is a 
nonbacteriostatic sulfonamide possessing a chemical structure and pharmacological activity 
distinctly different from the bacteriostatic sulfonamides. Acetazolamide is an enzyme inhibitor 
that acts specifically on carbonic anhydrase, the enzyme that catalyzes the reversible reaction 
involving the hydration of carbon dioxide and the dehydration of carbonic acid. Evidence seems 
to indicate that Acetazolamide has utility as an adjuvant in the treatment of certain dysfunctions 
of the central nervous system (CNS). Inhibition of carbonic anhydrase in this area appears to 
retard abnormal, paroxysmal, excessive discharge from CNS neurons. The diuretic effect of 
acetazolamide is due to its action in the kidney through the reversible reaction involving 
hydration of carbon dioxide and dehydration of carbonic acid. This reaction results in renal loss 
of HCO3 ions, which also carries out sodium, water, and potassium, leading to alkalinization of 
the urine and promotion of diuresis. Alteration in ammonia metabolism occurs due to increased 
reabsorption of ammonia by the renal tubules as a result of urinary alkalinization.  
 
It is a white to faintly yellowish white crystalline, odorless powder, weakly acidic, very slightly 
soluble in water and slightly soluble in alcohol. The chemical name for acetazolamide is N-(5-
Sulfamoyl-1,3,4-thiadiazol-2yl)-acetamide. As a carbonic anhydrase inhibitor that changes the 
intracellular pH, acetazolamide affects the transmembrane potential and conductance of 
potassium and calcium channels (Bain et al. 1992, Sappey-Marinier et al. 1999). While it has 
been studied more extensively in adults, it has been safely administered to children for a variety 
of indications at doses that range from 4 mg/kg/day to the lower of 100 mg/kg/day or 4000 
mg/day (Moffett et al. 2007, Distelmaier et al. 2006, Hacifazlioglu et al. 2012, Ko et al. 2010, 
Park et al. 2014, Per et al. 2013, Rangwala et al. 2007, Reiss et al.1996, Soler et al. 1998, 
Spennato et al. 2011, Standridge et al. 2010). 
 
Acetazolamide is an FDA-approved drug for adults for treatment of glaucoma, epilepsy, altitude 
sickness, and edema. FDA approved doses are in adults 250 to 1000 mg/day divided once to four 
times daily. A documented off-label use is for treatment of familial periodic paralysis. While the 
regular-release capsule is not FDA approved in children, it is used commonly in clinical practice 
and recommended doses have been established in children for management of glaucoma and 
seizures, reversal of metabolic alkalosis, and prevention and treatment of altitude sickness at 10-
30 mg/kg/day given in one to four divided doses. The extended released capsule is FDA-
approved in children with a max dose of 30 mg/kg/day or 1000 mg/day (Acetazolamide, 2020).  
 
Acetazolamide is contraindicated in cases of marked liver disease or dysfunction and in patients 
with cirrhosis because of the risk of development of hepatic encephalopathy and electrolyte 
imbalance. It is also contraindicated in patients with severe renal disease as it may potentiate 
acidosis and may cause CNS adverse effects in dialysis patients. It is contraindicated for 
individuals with carbonic anhydrase inhibitor hypersensitivity, sulfonamide hypersensitivity, 
electrolyte disturbances, and adrenal insufficiency. It has been reported to occasionally induce 


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bone marrow suppression and blood dyscrasias. It is an FDA pregnancy risk category C. These 
contraindications are reflected in our study exclusion criteria. 
 
In this study, regular-release acetazolamide will be dispensed in compounded capsule and 
compounded liquid formulations. 
1.3 
Clinical Data to Date 
 
Acetazolamide has previously been demonstrated to be efficacious in the treatment of ataxia 
symptoms in other genetic channelopathies including CACNA1A related disorder (Izquierdo-
Serra et al. 2018). Acetazolamide has also been demonstrated to improve the cerebellar 
symptoms of PMM2-CDG over a six-month pilot study. This initial clinical trial in 24 patients 
ages 5 to 20 years (mean age 12.3 ± 4.5 years, 9 females, 15 males) demonstrated that 
acetazolamide is well-tolerated and effective for motor cerebellar syndrome over six months in 
patients with PMM2-CDG (EudraCT 2017-000810-44). Subjects had statistically significant 
improvements in ICARS and Nijmegen Pediatric CDG Rating Scale (NPCRS) scores, and lower 
PATA rates. The PATA rate is the number of “pa – tas” an individual is able to speak in ten 
seconds. In this study, treatment with acetazolamide coincided with the gain of ability for some 
patients to sit and stand independently for a longer period of time, which caretakers rated to be 
an important clinical gain that significantly improved their quality of life and autonomy. Even 
patients with severe cerebellar atrophy (i.e., low MVRD) showed significant improvement in 
ICARS, demonstrating a potential therapeutic effect independent of structural cerebellar 
anomalies and atrophy. In fact, larger gains were observed in individuals with more severe ataxia 
demonstrated by higher baseline ICARS scores. There were no serious AEs related to the drug 
during the treatment. There was also no control group comparison, long term follow-up, nor 
ability to accurately titrate dose by mg/kg. An efficacious dosage of 22 mg/kg/day was 
established for optimal treatment response, although not all subjects were able to tolerate this 
dosage, leading to subject drop-out (Martinez-Monseny et al. 2019).  
 
Nine of the 18 items on the ICARS showed consistent improvement in patients on acetazolamide 
(items 1, 3, 5, 6, 8, 10, 13, 14, 15) (Martinez-Monseny et. al. 2019). These nine items constitute 
the “Mini-ICARS.” Data from the initial validation study was reanalyzed looking at the items in 
the Mini-ICARS, and explored the internal consistency of the Mini-ICARS scale formed by the 
sum of the nine items in thirteen PMM2-patients. In collaboration with the authors of the initial 
clinical trial, we explored the internal consistency of the Mini-ICARS scale formed by the sum 
of the nine items in thirteen PMM2-patients and found that Cronbach’s alpha was very high at 
0.96 by analyzing this subset data from the 2015 and 2017 ICARS validation studies. 
Additionally, the agreement of scores between three different evaluators of the Mini-ICARS 
from analysis of the 2015 and 2017 ICARS validation studies again showed a correlation very 
close to 1, demonstrating the Mini-ICARS is also valid in PMM2-CDG (Serrano et. al. 2015, 
2017, personal communication). The Mini-ICARS comprehensively captures the areas of 
clinically significant improvement, while being much shorter to implement, decreasing the 
likelihood of testing fatigue and inability to complete clinical testing in subjects. Thus, we chose 
the Mini-ICARS to be the primary endpoint for this trial. 


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1.4 
Dose Rationale 
Due to the potential of subject intolerance to the most efficacious dose of acetazolamide at 
22 mg/kg/day as demonstrated by the initial clinical trial, which is well within the FDA-
approved dosage, we will titrate up from a lower dose to increase tolerability, as is typical in 
clinical practice. The dose of study drug will be initiated at 7.58 mg/kg/day and increased to a 
maximum of 30 mg/kg/day (not to exceed 1000 mg/day) if well tolerated with no AEs or 
abnormal pH. If the pH is <7.3 and/or bicarbonate <21, the dose will be reduced per table 1. This 
is based on the cruder dose titration used by Martinez-Monseny et. al. 2019, as well as standard 
accepted doses for acetazolamide for other indications. Subjects will remain on their highest 
tolerated dose, not to exceed 30 mg/kg/day or 1000 mg/day. While 22 mg/kg/day was the goal 
dose in the Martinez-Monseny study, and there was a non-statistically significant trend towards 
greater ICARS improvement to higher doses, the mean tolerated dosage was 13 mg/kg/day with 
a range of 6.8-16.7 mg/kg/day, and subjects even on the lower end of this range derived some 
improvement in ICARS with doses as low as 7.58 mg/kg/day (Martinez-Monseny et al. 2019, 
personal communication – data summarized in Table 0a).  
 
Table 0a 
ID  
Gender/ 
Age*  
Molecular findings  
MVRD  
ICARS  
VO  
ICARS  
V25  
Responder/  
Withdrawal  
ICARS  
V30  
Dose/  
Kg 
25wk  
1  
F  
11.0  
c.338C>T  
c.353C>T+c.550C>A  
35 %  
63  
58  
Yes/AZA  
56  
16,67  
2  
F  
12.5  
c.470T>C  
c.484C>T  
46 %  
33  
24  
Yes/NO  
27  
12,82  
3  
F  
14.9  
C.95TA>GC  
C.256-1G>C  
52 %  
12  
8  
Yes/AZA  
4  
11,90  
4  
F  
8.8  
c.368G>A  
c.722G>C  
50 %  
16  
12  
Yes/AZA  
8  
16,67  
5  
M  
19.3  
c.278A>C  
c.422G>A  
69 %  
4  
2  
Yes/NO  
4  
15,31  
6  
F  
18.9  
c.367C>T  
c.458T>C  
29 %  
59  
48  
Yes/AZA  
47  
16,06  
7  
M  
8.9  
c.422G>A  
c.710C>T  
45 %  
56  
50  
Yes/AZA  
50  
16,30  
8  
M  
6.0  
c.338C>T  
c.710C>A  
ND  
PC  
PC  
Yes/NO  
PC  
15,63  
9  
M  
16.9  
c.422G>A  
c.470T>C  
36 %  
56  
51  
Yes/NO  
53  
6,80  
10  
M  
18.4  
c.422G>A  
c.722G>C  
ND  
12  
7  
Yes/NO  
8  
9,68  
11  
M  
14.3  
c.131T>C /Alu retrotrasp 
28 kb deletion exon 8  
37 %  
55  
48  
Yes/AZA  
48  
15,63  
12  
M  
8.3  
c.710C>T  
c.470T>C  
36 %  
69  
52  
Yes/AZA  
50  
16,45  
13  
M  
10.1  
c.95T>G  
c.422G>A  
51 %  
14  
8  
Yes/NO  
13  
7,58  


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Investigator: Dr. Marc C. Patterson CONFIDENTIAL 
 
 
 
Additionally, longer term safety of acetazolamide in the pediatric population, while not formally 
assessed in a clinical trial, has accumulated, and been published post drug approval.  This safety 
data is summarized in the below Table 0b.
14  
M  
18.3  
c.710C>G  
c.710C>G  
55 %  
8  
4  
Yes/NO  
5  
11,36  
15  
M  
20.0  
c.368G>A  
c.548T>C  
34 %  
58  
51  
Yes/AZA  
55  
12,82  
16  
M  
6.0  
c.191A>C  
c.422G>A  
48 %  
67  
61  
Yes/NO  
68  
15,15  
17  
M  
8.6  
c.193G>T  
c.422G>A  
33 %  
76  
65  
Yes/AZA  
64  
16,74  
18  
M  
5.8  
c.415G>A  
C.620T>C  
30 %  
66  
60  
Yes/AZA  
58  
16,67  
19  
F  
11.3  
c.470T>C  
c.722G>C  
46 %  
15  
11  
Yes/NO  
17  
12,50  
20  
M  
13.2  
c.484C>T  
c.523+3A>G  
56 %  
14  
10  
Yes/NO  
18  
10,71  
21  
F  
12.2  
c.193G>T  
IVS-9T>G  
48 %  
56  
55  
No/-  
57  
8,47  
22  
F  
13.7  
c.640-9T>G  
c.710C>T  
58 %  
46  
48  
No/-  
47  
8,43  
23  
M  
7.8  
c.44G>A  
c.422G>A  
ND  
79  
NC  
No/-  
NC  
8,06  
24†  
F  
13.5  
c.722G>C  
c.470T>C  
31 %  
NC  
-  
-  
-  
  


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Table 0b 
Study 
Author & 
Link to 
Pubmed 
Year of 
Publication 
Patients 
(n) 
Indication; Age 
range (years) 
Study Design 
Route;Formulation; 
Dose (mg/kg/d); 
Duration of 
therapy 
Adverse Events 
Efficacy Endpoint, 
Magnitude of Change 
Lombroso 
et al. 
(13278187) 
1956 
126 
(106 
<=19 
yr) 
Epilepsy;  82  
patients <12, 
24 patients 
between 12-
19  
Open label 
Oral; tablets; 8-30 
; 3 months to 3 
years 
None – “side effects – drowsiness 
19, anorexia 17, irritability 11, 2-5 
for rest: rash, tingling, dizziness, 
poor behavior, enuresis, vomiting, 
ataxia, hyperpnea” 
Seizure frequency, 
complete control 
34/126, 90-99% 
reduction 12/126. 
Forsythe 
et al. 
(6797857) 
1981 
54 
Epilepsy; 3-14 
10-15; 2 years 
None 
Oles et al. 
(2492225) 
1989 
48 
Epilepsy; 6-64  ?Open label Oral; unspecified 
(Unspec); 3.8-22; 
3-30 months 
(mean 12.9) 
None 
Seizure frequency, 
50% decrease = 
responders – 44% = 
responders 
Futagi et 
al. 
(8972532) 
1996 
17 
Epilepsy or 
Febrile 
Seizures; 1.2 
to 5.4 (mean 
2.6) 
Open label 
longitudinal 
Unspec; unspec; 
3.3-15.8 (mean 
9.5); 1.2 to 6.9 
years (mean 3.5 
years) 
Poor growth (weight and height) in 
7/10 patients – not associated with 
bicarb level; resolved after drug 
withdrawal 
None 
Katayama 
et al. 
(11934510) 
2002 
37 
Refractory 
Epilepsy; 1 to 
17 (mean 8 
years 1 
month) 
Open label 
?oral; unspec; 10-
20; 10 months 
and 14 yrs 8 mo 
(mean 6 years 
5mo) 
Only one patient had a history of 
passing a stone at the age of 21 
while he was taking AZA. No other 
serious side effects due to AZA. 
Some patients experienced 
transient drowsiness when starting 
on AZA 
Seizure frequency, 
50% decrease in 
frequency 


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Sharan et 
al. 
(20130709) 
 2009 
22 
Glaucoma; 2 
months to 15 
years (mean 
6.4 years), at 
end of study 
2.0 to 18.8 
years (mean 
9.4 years) 
Retrospective 
chart review 
Oral; unspecified; 
15–20; 5 months 
to 7.6 years 
(mean 1.5 years) 
Two patients (9%) crossed 2 lines in 
percentile growth charts for weight, 
one was diagnosed with Sturge-
Weber. Pt 1 (7.2yrs at time of 
discontinuation) pH 7.29, pCO2 38, 
bicarb 18. Pt 2 7.32, pCO2 32, bicarb 
16. CBC normal.  
  
Eleven patients (11/22, 50%) 
showed a decline in z score for 
weight over the follow-up period, 
and the remainder showed an 
increase, for an overall estimate of 
slope in this population of 0.01 
(95% confidence limits [CL]: 
–0.08, 0.11), which was not 
significant (p 5 0.8). 
None 
Markhorst 
et al. 
(25042881) 
2014 
3 
Nondystrophic 
myotonia; 10-
17 
Open label 
case series 
?oral; 
unspecified; 200-
1000 mg/d (unk 
weight); 4-10 
years 
Headache with high doses (1000 
mg/d). 
Improvement of 
muscle stiffness and 
speech,  which 
recurred with 
withdrawal of 
treatment.  
Martinez-
Monseny 
et al. 
(30873657) 
2019 
24 
Ataxia in 
PMM2-CDG; 
6-20.0 (mean 
12.4) 
Open label; 
randomized 
withdrawal 
Oral; tablets; 8-
30; 25-30 weeks 
9 showed abnormally low 
bicarbonate, 2 showed asthenia, 
and 2 showed asthenia and 
paresthesia.  
ICARS score; 3. 


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1.5 
Risks and Benefits 
Risks 
In general, acetazolamide is considered a safe drug. Per the package insert, severe adverse 
reactions that have been reported with administration of acetazolamide include seizures, muscle 
paralysis, hepatic necrosis, hepatic failure, hepatic encephalopathy, toxic epidermal necrosis, 
agranulocytosis, anaphylaxis, aplastic anemia, hemolytic anemia, Stevens-Johnson syndrome, 
pancytopenia, acute generalized exanthematous pustulosis, renal failure, and renal tubular 
obstruction. The incidence of each reaction is unknown. It is likely that individuals who have 
significant baseline allergy to acetazolamide and other components, hepatic dysfunction, blood 
dyscrasias, and/or renal dysfunction would be at higher risk for these severe reactions. Thus we 
are assessing for hepatic dysfunction, renal dysfunction, allergy, and blood dyscrasias at baseline 
and excluding individuals with significant disturbances in their laboratory assessments or have a 
history of allergy to the components of the therapeutic agent or placebo (as defined by the 
exclusion criteria below). We will monitor complete blood count (CBC), liver function tests 
(LFT), venous blood gas (VBG or bicarbonate/CO2), electrolytes, and creatinine, and urinalysis 
with urine creatinine, calcium, and protein at baseline and regularly throughout the study, and if 
any individual meets exclusion criteria at any point during the study, we will terminate their 
treatment. Patients may develop acidosis on acetazolamide therapy, which may lead to inability 
to continue the therapy longer or a decrease in dosage. Acetazolamide has been associated with 
growth suppression in pediatric patients, although not all individuals have been reported to have 
poor growth and the dosages associated with growth suppression have not been consistent. 
Growth has been reported to resume and improve after discontinuation of acetazolamide. We 
will monitor growth parameters (height, weight, head circumference) regularly throughout the 
study and tailor their management and continuation in the study on a case by case basis. We will 
monitor patients’ acid/base status and titrate acetazolamide accordingly. We will also obtain a 
one-time measurement of acetazolamide serum concentration at steady state at the six-month 
visit.  
 
Other less severe side effects may include depression, confusion, ataxia, hyperglycemia, 
hypoglycemia, glycosuria, jaundice, elevated hepatic enzymes, hyperuricemia, hemolysis, 
thrombocytopenia, leukopenia, hyperchloremia, hyponatremia, crystalluria, hypokalemia, 
nephrolithiasis, hematuria, myopia, growth inhibition, melena, dizziness, paresthesias, fatigue, 
drowsiness, malaise, headache, photosensitivity, urticaria, fever, polyuria, diarrhea, anorexia, 
xerostomia, nausea, vomiting, dysgeusia, flushing, tinnitus, and purpura. These symptoms are 
also all monitored during each visit by history and laboratory studies. Subjects may voluntarily 
withdraw at any time from the trial. 
 
Benefits 
We anticipate that subjects on active treatment will have improved quality of life due to 
lessening ataxia given the preliminary findings in previous studies. From a scientific standpoint, 
we anticipate that this study will evaluate the efficacy of acetazolamide as a therapeutic agent for 
ataxia in PMM2-CDG.  


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Risk/Benefit Assessment 
The risks to subjects are reasonable in relation to the anticipated benefits because the major risks 
are not universal, closely monitored for, and would lead to study withdrawal. The majority of the 
risks can be treated medically and are likely to resolve after discontinuing therapy. The potential 
benefits for participating subjects and medical knowledge are clinically significant. Amelioration 
in ataxia will significantly improve the subject’s quality of life, and possibly allow for 
downstream gains in learning and development. The gain in knowledge will allow for healthcare 
providers to make informed decisions about utilizing this therapeutic in this population. It may 
also be the groundwork needed to add an FDA-approved indication for the use of acetazolamide 
in PMM2-CDG. This would be the first FDA-approved therapeutic agent for PMM2-CDG, 
which would be a major breakthrough for this disease and other closely related ultra-rare genetic 
disorders. 
2 Study Objectives 
 
Objective 1 (Primary): 
To evaluate the efficacy of acetazolamide in improving ataxia in patients with PMM2-
CDG. 
To achieve this goal, we will compare the change of Mini-ICARS score from baseline to after six 
months post-randomization of treatment between the placebo and active treatment groups.  
Objective 2 (Secondary): 
To evaluate for any adverse events related to longer term acetazolamide administration. 
To achieve this goal, we will monitor changes on physical exam, laboratory studies that are 
likely to be affected by acetazolamide therapy including blood pH and electrolyte balance, and 
urine calcium excretion regularly through the duration of the trial. We will determine the 
percentage of patients treated with acetazolamide who experience (a) drug related adverse 
event(s) and (b) drug related serious adverse event(s) while they are on blinded therapy as well 
as for the duration they remain in the open label extension. 
 
Objective 3 (Secondary): 
To examine the effect of acetazolamide on PMM2 biomarkers including carbohydrate 
deficient transferrin, electrolytes (Na, K, Cl, CO2), VBG (pH, pCO2, PO2, CO2, Base 
excess) or bicarbonate/CO2, 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.  
We will collect these data at baseline and after 6 months of placebo or treatment and identify 
changes from baseline. We will analyze if there is a difference of changes between the treatment 
and placebo group. We will also compare baseline measurements to the last measurement 
obtained as part of the open label extension and determine if there are changes to these 
measurements. 
 
Objective 4 (Secondary): 


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To explore characteristics of individuals with PMM2-CDG who do not respond to 
acetazolamide. 
In addition to analyzing our data for effect, we will perform subgroup analysis based on 
genotype, ataxia severity, baseline NPCRS score, sex, concomitant therapies, results of 
transferrin isoform analysis, concomitant medical problems/diagnoses, number of previous 
hospitalizations, ages at diagnosis, baseline laboratory test results, age at developmental 
milestones achievement, baseline developmental/educational achievement, baseline frequency 
and type of therapies, and baseline support needed for activities of daily living to determine if 
there are particular subgroups that are less responsive to therapy. 
3 Study Design 
3.1 
General Description 
This study is a 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 
biallelic pathogenic or likely pathogenic variants in PMM2 OR biallelic variants of uncertain 
significance, pathogenic, or likely pathogenic variants in PMM2 AND  Enzymatic confirmation 
of PMM2 enzyme deficiency 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 dose of placebo 
twice daily by mouth. Initial dose of acetazolamide is at least 7.58 mg/kg/day per Table 1 . If the 
pH is <7.3 and/or bicarbonate <21, a value associated with mild metabolic acidosis, the dose will 
be reduced per table 1. 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 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 number 
of capsules will be as per Table 1, and 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 5 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 5 per table 1 and titrated upwards in the same manner in 
Visits 6, 7 and 8 (remote) as in Visits 2, 3 and 4 (remote). Subjects will have the option to 
withdraw from the study any time after Visit 5 if they do not wish to proceed onto or continue 
with the open label phase. 
3.2 
Number of Subjects 
 
We aim to enroll 26 evaluable patients. Up to 7 additional patients will be enrolled to account for 
a 20% loss in sample size due to ineligibility, major treatment violation, cancellation, or 
withdrawal prior to completion of the 6-month blinded phase of the study. Maximum projected 
accrual is, therefore, 33 patients. Enrollment will continue until the 26th evaluable patient 
completes the blinded phase.  Enroll will pause when 26 patients have either completed or are 


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actively completing the blinded phase; enrollment will reopen if any of these patients withdraw 
before completing the blinded phase. 
3.3 
Duration of Participation 
 
The duration of participation is a maximum of approximately 1.75 years as outlined in Figure 1 
below.  
 
Figure 1. Study Timeline for visits 1 through 9 
3.4 
Primary Study Endpoints 
 
Primary Endpoint: Change in Mini-ICARS score from baseline to 6 months. 
3.5 
Secondary Study Endpoints 
 
Secondary Endpoints: Biomarkers, testing scores, and rating scales at 6 months. These 
biomarkers and scores include carbohydrate deficient transferrin results (Mono/Di, A/Di, Apo 
CIII1/Apo C III2, Apo CIII0/Apo CIII2), electrolytes (Na, K, Cl, CO2), VBG (pH, pCO2, PO2, 
CO2, Base excess) or bicarbonate/CO2, liver function tests (AST, ALT, GGT, indirect and direct 
bilirubin, total protein, albumin, alkaline phosphatase), coagulation factors (prothrombin time, 
coagulation factor XI, and antithrombin), kidney function tests (BUN, Creatinine, Urinalysis, 
urine calcium/creatinine ratio, urine protein/creatinine ratio), bone mineral metabolism markers 
(serum bone-specific alkaline phosphatase (BSAP) and carboxy-terminal collagen crosslinks 
(CTX), Calcium, Phosphorus, Vitamin D, and parathyroid hormone (PTH)), growth (height, 
weight, head circumference), vital signs (blood pressure, respiratory rate, heart rate), PROMIS 
scores, the PATA score, and NPCRS score. 
3.6 
Primary Safety Endpoints 
 


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The primary safety endpoint is incidence of (a) drug related adverse event(s) and (b) drug related 
serious adverse event(s) while patients are on blinded therapy as well as for the duration they 
remain in the open label extension. 
3.7 
Identification of Source Data 
 
The following data will be collected:  
• Date of visit 
• Age at visit (Years, Months, Days) 
• Vital signs: systolic and diastolic blood pressures (mmHg), heart rate (beats/minute), 
respiratory rate (breaths/minute), temperature (degrees C) 
• Growth Data: length/height (cm), weight (kg), head circumference (cm) 
• Physical Exam: brief neurologic exam, cardiovascular exam, abdominal exam, (HEENT) 
head ears eyes nose throat exam, dermatologic exam, pulmonary exam, musculoskeletal 
exam (Normal/Abnormal with text field to explain abnormality) 
• PATA score 
• AE and SAEs defined by the CTCAE version 5 (specific AE/SAE and date; see 
Appendix D) 
• PROMIS Questionnaires (Appendix C) 
• Mini-ICARS (Appendix B) 
• NPCRS (Appendix A) 
• Drug volume prescribed (ml/day or number of capsules/day) 
• Laboratory values, normal ranges, and units: CBC (WBC, Hgb, Hct, Plt, % Neutrophils, 
% Lymphocytes, % Eosinophils, % Basophils, % Monocytes, %Bands, MCV, MCHC, 
MCH), electrolytes (Na, K, Cl, CO2), VBG (pH, pCO2, PO2, CO2, Base excess) or 
bicarbonate/CO2, liver function tests (AST, ALT, GGT, indirect and direct bilirubin, total 
protein, albumin, alkaline phosphatase), coagulation factors (prothrombin time, 
coagulation factor XI, and antithrombin), kidney function tests (BUN, Creatinine, 
Urinalysis, urine calcium/creatinine ratio, urine protein/creatinine ratio) 
• BSAP, CTX, calcium, phosphorus, vitamin D, and PTH at baseline and visit 5. 
• Plasma/Serum Acetazolamide level at visit 5. 
• Physical therapy, Occupational therapy, Speech therapy, Feeding therapy – (yes/no if 
ongoing, number of sessions per month) 
• Annual screening ophthalmological exam including intraocular pressure testing. 
 
The following source data will be captured in supportive documentation (e.g. study source 
documents, EMR): 
• Clinical interpretation of laboratory values 
• Medication review and adherence 
• 
Video of the Mini-ICARS assessment 


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4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
 
• At minimum, 4 years of age at Visit 1 
• Biallelic pathogenic or likely pathogenic variants in PMM2 
OR 
Biallelic variants of uncertain significance, pathogenic, or likely pathogenic variants in 
PMM2  AND  Enzymatic confirmation of PMM2 enzyme deficiency 
• Affected with ataxia evidenced by Mini International Cooperative Ataxia Rating Scale 
(Mini-ICARS) score >0 at baseline 
• Parent or legal guardian available to provide consent on behalf of minor subjects or adult 
subjects who are unable to give informed consent due to developmental disabilities. 
Willingness of subject or legal guardian to provide consent. 
• If female and >10 years old, willing to practice abstinence or using an effective 
contraceptive regimen that is constituted by two acceptable effective methods of 
contraception, including a barrier method such as a condom or occlusive cap (diaphragm 
or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository and an 
established non-barrier method such as oral, injected, or implanted hormonal methods, an 
intrauterine device (IUD), or intrauterine system for the entire duration of the treatment 
period and for at least 28 days after receiving the last study drug dose. Sterilized or 
infertile subjects (defined as having undergone surgical sterilization, ie, bilateral 
tubectomy, hysterectomy and bilateral ovariectomy or as being postmenopausal, defined 
as at least 12 months of amenorrhea prior to enrollment) will be exempted from the 
requirements to use contraception in this study. 
 
4.2 
Exclusion Criteria 
 
• Hepatic impairment defined as AST/ALT >3.0 - 5.0 x ULN if baseline was normal; >3.0 
- 5.0 x baseline if baseline was abnormalin the last 12 months 
• Renal impairment defined as serum creatinine 1.5-1.9 times ULN for age OR ≥ 26.5 
umol/l increase from ULN for age 
• Hypokalemia 
• Hyponatremia 
• Hyperchloremic acidosis 
• Adrenal insufficiency  
• 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, other Carbonic Anhydrase Inhibitors, Phenytoin, Primidone, folic acid 
antagonists, antidiabetic agents, quinidine, lithium, cyclosporine, sodium bicarbonate. 


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• Participation in another therapeutic trial - the subject will not be permitted to participate in 
any other drug trial during the blinded phase and during the 28 days prior to Visit 1 
• Pregnant (positive urine beta-HCG test) or nursing (by history) women 
• Weight <10 kg 
4.3 
Subject Recruitment, Enrollment and Screening 
 
• Patients seen clinically by genetics at Seattle Children's, CHOP, and Mayo Clinic with 
molecularly and/or enzymatically-confirmed diagnosis of PMM2-CDG will be 
approached for consent. Additional patients may be consented if referred by an external 
provider to the genetics clinic. If an individual fails screening, they can be rescreened 4 
or more months after their initial screening. Subjects’ treatment may be paused or 
discontinued if the study drug is found to be harmful such as development of kidney or 
hepatic failure or insufficiency as measured by renal and hepatic function labs, 
respectively.  If abnormal values are noted as defined in section 8.1 and no other cause 
for these laboratory changes are likely, then drug will be stopped, and repeat labs will be 
obtained at reasonable intervals per investigator’s clinical judgement after 
discontinuation until labs have normalized to stabilized. Treatment may be restarted if 
labs have returned to baseline using the same ramp up schedule as described for visits 2, 
3 and 4. 
4.4 
Subject Withdrawal Criteria 
• Failure of subject to adhere to protocol requirements 
o If a patient is unable to adhere to study procedures, they may be withdrawn from 
the study by the investigator per investigator discretion. 
• Subject decision to withdraw from the study (withdrawal of consent) 
o A patient or patient’s family/guardian may withdraw consent at any time and 
cease administration of study drug or placebo. They may be asked to return for 
follow up testing to ensure that laboratory values are satisfactory (see schedule of 
events table (SOE)) and please refer to section 6.10. 
 
 
5 Study Drug  
5.1 
Description 
 
Name and detailed description of the investigational product(s) 
• Acetazolamide is an inhibitor of the enzyme carbonic anhydrase. It is a white to faintly 
yellowish white crystalline, odorless solid, weakly acidic, very slightly soluble in water 
and slightly soluble in alcohol. The chemical name for acetazolamide is N-(5-Sulfamoyl-
1,3,4-thiadiazol-2yl)-acetamide. The acetazolamide formulations used in our study will 
be capsules. 


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o Acetazolamide 250 mg oral capsules: will be compounded by over-encapsulating 
acetazolamide 250 mg tablet within a gelatin capsule and filled with lactose 
powder. 
• Placebo (to match Acetazolamide) 
o Placebo capsules: to be compounded by filling empty gelatin capsules with 
lactose powder to match Acetazolamide capsules. 
 
 
5.2 
Treatment Regimen 
 
Acetazolamide dosages will be calculated based on weight and will be administered orally or 
enterally (i.e., via gastric-tube, nasogastric tube, etc.) as capsules with food in gradually 
increasing dosages according to Table 1 below. Subjects <10 kg will be excluded from the study. 
Missed doses will be documented but will not be re-dosed. Patients will resume their original 
scheduled dosing per protocol. Blinding will be maintained by having specifically affected 
laboratory markers (e.g., bicarbonate level, pH) being monitored by an unbiased clinician who is 
not part of the study.  
 
Table 1. Capsule formulation Acetazolamide Dosages, oral administration divided BID 
Subject 
weight (kg) 
Dose 1 
Dose 2 
Dose 3 
mg/day 
mg/kg/day 
mg/day 
mg/kg/day 
mg/day 
mg/kg/day 
>10 - <16.4 
125 
6.3-12.5 
250 
12.5-25 
250 
12.5-25 
16.4 - <33 
250 
7.1-12.5 
375 
10.7-18.75 
375 
14.4-25 
33 - <41 
250 
5.6-7.1 
500 
11.1-14.3 
750 
16.6-21.4 
≥41 
375 
<8.3 
750 
<16.7 
1000 
<22.2 
 
Initially individuals will be started on Dose 1 or the volume equivalent of placebo after 
randomization. The therapy will be mailed to the subject after randomization or the subject will 
pick it up at the site designated by the investigational pharmacy. Subjects should start the therapy 
by week 1.5 after visit 1. At Visits 2, 3 and 4 doses will be adjusted for both acetazolamide and 
placebo (volume equivalent in placebo for dosages either in ml or # caps) as follows:  
• If no related or likely related AE or SAE and pH is ≥7.3 and/or bicarbonate ≥ 21,  
o if current dose is at dose 1, dose will be advanced from dose 1 to dose 2; 
o if current dose is at dose 2, dose will be advanced from dose 2 to dose 3; 
o if current dose is at dose 3, dose will remain at dose 3. 
• If no related or likely related AE or SAE and pH is ≥7.3 and/or bicarbonate < 21, 
o dose will remain at current dose. 
• If pH is <7.3 and/or bicarbonate <21 and no related or likely related AE or SAE  
o if current dose is at dose 1, drug or placebo will be discontinued; 
o if current dose is at dose 2, dose will be decreased from dose 2 to dose 1; 
o if current dose is at dose 3, dose will be decreased from dose 3 to dose 2 or dose 1 
if dose 2 and 3 are the same. 


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• If the investigator becomes aware of a likely related or related SAE, based on clinical 
judgement, the subject may be discontinued from placebo or drug. If an SAE occurs, the 
investigator will report the SAE to the DSMB. The DSMB will decide whether 
unblinding is necessary and convey their decision to the local study team, who will then 
implement the decision. 
 
At Visit 5 (26 weeks) a discussion with the subject regarding whether they would like to proceed 
into the open label extension with acetazolamide will occur. If continuation is preferred, they 
will be restarted on dose 1 since we are not certain if they were on treatment or placebo. At 
subsequent visits after visit 5, acetazolamide will be modified in the same manner as above. If 
not, then neither drug nor placebo will be given to the patient. As this is an open label 
continuation, acetazolamide will be dispensed by a clinical pharmacy. 
 
5.3 
Method for Assigning Subjects to Treatment Groups 
 
• After informed consent, randomization will occur as a tiered approach based on age 
(group 1 <12 years, group 2 ≥ 12 years) and Mini-ICARS score (group a score <25, 
group b ≥ 25 points) to give 50/50% to placebo/drug, respectively. If a Mini-ICARS was 
performed and recorded <1 year prior to enrollment, randomization can be based on that 
historic score. The randomization scheme will be generated by a statistician that is not 
part of the study team and will be provided to the applicable research pharmacy. 
5.4 
Preparation and Administration of Study Drug 
 
• The study drug and placebo will be compounded by the research pharmacy at each 
institution.  
• A member of the study team will pick up the drug/placebo from the pharmacy and deliver 
it to the investigator meeting with the patient. The investigator will educate the patient on 
proper administration of the drug/placebo (number of times per day to take the drug, 
amount for each administration) and answer any questions or concerns the 
patient/patient’s parent or guardian may have. The study drug may also be mailed to 
subjects at their address of residence. 
• The research pharmacy will obtain the study drug and have the production lab over 
encapsulate the drug and placebo for blinding purposes.  
 
 
 
Table 2: Formulation of Acetazolamide and Placebo 
 
ORAL CAPSULE 
FORMULATION 
Acetazolamide 250 mg Capsules 
Placebo Capsules 
Active ingredient 
Acetazolamide 250 mg tablets (any 
commercially available generic brand) 
N/A 
Empty Gelatin Size 0 capsules 
 
TBD 
TBD 


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Lactose USP powder 
Quantity sufficient to fill capsule 
Quantity sufficient to fill 
capsule 
5.5 
Subject Compliance Monitoring 
 
Subjects and/or their caregivers will be asked to keep a patient diary noting the date they take 
their study drug and any adverse events. They will be asked to bring their patient diary to each 
study visit along with all used and unused study drug containers.  
 
If a subject is significantly non-compliant, as per the investigator’s discretion, with the study 
drug regimen, the investigator will discuss with the patient the reasons that the drug is not being 
taken as requested. Missed doses will be recorded. If this discussion does not improve the 
subject’s compliance to greater than 50% of the doses taken per week by the next study visit, 
they are encouraged to adhere to the study medication schedule.  
5.6 
Prior and Concomitant Therapy 
 
• All concomitant medication and concurrent therapies (physical therapy (PT)/occupational 
therapy (OT)/speech therapy (ST)/feeding therapy (FT)) will be documented at baseline 
and at each visit (from 30 days prior to the first dose). 
o Medication trade name; 
o Indication for which the medication was given; 
o Dose/strength, route, and frequency of administration; 
o Date started and date stopped (or continuation at study exit). 
• All medications that do not have a high risk of serious reactions will be permitted while 
on the study.  Any medication listed as an exclusion criterion is not permitted while on 
the study (i.e., Mecamylamine, Sodium Phosphates, Salicylates, Mefloquine, 
Methenamine and other Carbonic Anhydrase Inhibitors).  
• If a subject has started taking a prohibited medication on the exclusion criteria, they will 
be discontinued from the study. If a subject is started on a medication that has a high risk 
of serious reaction, continued participation in the study will be decided on a case-by-
case-basis. 
5.7 
Packaging 
Packaging, labeling, taste, and appearance of test and control treatments will be very similar to 
maintain the blind. Active drug concentrations will be prepared by the pharmacy prior to handoff 
to clinicians or families for administration. Both the study drug and comparator will be labeled 
with the same label “Acetazolamide or Placebo” or per institution standards as well as “Limited 
by Federal Law to Investigational Use Only.” Drug products will be packaged in standard 
pharmacy containers with child resistant closures for outpatient use (e.g. amber HDPE bottles or 
prescription vials). 
 
5.7.1  Blinding of Study 
 


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• Investigators, study staff in contact with patients, and subjects will be blinded. The 
research pharmacy will then dispense acetazolamide or placebo to the patient or study 
staff. Access to the randomization code will be strictly controlled by the research 
pharmacy and DMCC. Packaging, labeling, and appearance of the test and control 
treatments will be similar to maintain the blinding. Active drug concentrations will be 
prepared by the pharmacy prior to handoff to clinicians or patients/caretakers for 
administration. The study will proceed to open label continuation at Visit 5 (Week 40-
56). During the study, the blind may be broken only in emergencies when knowledge of 
the patient’s treatment group is necessary for further patient management. If the blind is 
broken for a subject, that individual will be removed from the blinded portion of the 
study.  If a subject experiences an adverse event warranting unblinding procedures, the 
pharmacy will inform the physician of the prescribed treatment.  
 
After all data are collected for the blinded portion of the study and all data cleaning is 
completed for these data, the data base for the blinded portion of the study will be locked 
and the study will be unblinded for analysis. 
5.8 
Receiving, Storage, Dispensing and Return 
5.8.1 Receipt of Drug Supplies 
 
Acetazolamide is an FDA-approved, commonly available drug. The research pharmacy will 
order the drug and prepare the proper dosage.  
5.8.2 Storage 
• The research pharmacies are in secure locations only accessible to credentialed staff 
members with badge access.  
5.8.3 Dispensing of Study Drug 
 
Regular study drug reconciliation will be performed to document drug assigned, drug dispensed, 
drug returns, and drug remaining.  This reconciliation will be logged on the drug reconciliation 
form, signed, and dated by the study team/research pharmacist. 
5.8.4 Return or Destruction of Study Drug 
 
In accordance with federal regulations (21CFR 312.62), all Investigators are required to keep 
accurate records showing final disposition of all investigational drugs and placebo. 
 
Investigational drugs are to be used only in accordance with this protocol and under supervision 
of the Study Pharmacist or a duly designated person. An accurate drug disposition record will be 
kept at each site, specifying the amount dispensed and the date of dispensation. This inventory 
record must be available for inspection at any time. Copies of this record will be available for 
monitoring boards upon request.  
 


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After the study is completed, the Study Pharmacist must account for all drug used, unused and 
partially used. Unused study medication from the study site will be returned to either the 
investigator or Study Pharmacist and destroyed. Drug destroyed on site will be documented in 
the study files.  
 
6 Study Procedures 
 
Prior to participating in the study, written approval of the protocol and informed consent must be 
obtained from the IRB.  
 
Informed consent:  
The investigator or designated study coordinator will explain the study to the patient and/or 
parents/guardian of the patient. Study purpose, procedures, risk, and benefits will be discussed. 
Patient/parents/guardians willingness and ability to meet the follow up requirements will be 
determined and written informed consent will be obtained. The investigator/study coordinator 
will also sign and date the consent form. The original informed consent form will be retained 
with the subject records; a copy will be provided to the patient/parent/guardian. Informed 
consent will be obtained prior to any procedures or data collection. 
 
Subject Identification: 
Ethical and confidential research standards will be maintained. The minimum necessary 
protected health information will be used in study records. Computer records of data will be 
password protected behind institutional information technology security firewalls. All 
information will be treated with strict adherence to professional standards of confidentiality.  
 
The following is a detailed list of study visits from screening to final follow-up and the required 
procedures/tests.  
 
6.1 
Visit 1 – Week 0 
• Screening for eligibility 
• Informed consent; no procedures will occur until informed consent and eligibility criteria 
are confirmed. 
• Interview elements: 
o Medical history (past and current medical conditions, past surgical history) 
o Clinical history (history of present illness, any assessments)  
o Concomitant medication review 
o Ongoing therapies (physical therapy (PT), occupational therapy (OT), speech 
therapy (ST), feeding therapy (FT)) 
• Procedural elements: 
o Physical exam: Vital signs – temperature, systolic and diastolic blood pressures 
(mmHg), heart rate (beats/minute), respiratory rate (breaths/minute), Growth Data* 
- length/height (cm), weight (kg), head circumference (HC in cm), Exam by 
systems – (normal/abnormal) brief neurologic exam, cardiovascular exam, 


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abdominal exam, (HEENT) head ears eyes nose throat exam, dermatologic exam, 
pulmonary exam, musculoskeletal exam  
o Mini-ICARS  
o PATA 
o NPCRS 
o Blood collection** (CBC (WBC, Hgb, Hct, Plt, % Neutrophils, % Lymphocytes, 
% Eosinophils, % Basophils, % Monocytes, % Bands, MCV, MCHC, MCH), 
electrolytes (Na, K, Cl, CO2), VBG (pH, pCO2, PO2, CO2, Base excess) or 
bicarbonate/CO2, liver function tests (AST, ALT, GGT, indirect and direct 
bilirubin, total protein, albumin, alkaline phosphatase, calcium, phosphorus, 
vitamin D, parathyroid hormone), coagulation factors (prothrombin time, 
coagulation factor XI, and antithrombin) kidney function tests (BUN, Creatinine), 
CTX, BSAP 
o Urine collection (Urinalysis, urine calcium/creatinine ratio, urine protein/creatinine 
ratio, HCG for females)  
• Survey given to families to complete and returned to site at or after visit by mail or 
electronically 
o PROMIS 
• Performed after visit once inclusion and exclusion criteria are met and Mini-ICARS score 
established 
o Randomization 
o Dose Initiation – Investigational pharmacy to dispense to patient/caregiver by mail 
or in person at previously designated location by pharmacy. Investigator or 
pharmacist to instruct patient/caregiver regarding administration of drug or placebo 
via phone call, telehealth, or in person. 
*Growth data including length/height (cm), weight (kg), head circumference (HC in cm) 
will be measured or measured at home and reported by subjects at least every 12 weeks. 
**Total blood volume drawn will not exceed 5% of total blood volume of the child over 
24-hour period, and 10% of total blood volume of the child over 8 weeks. 
6.2 
Visit 2 (Remote)– Week 2-3 
• Procedural elements 
o Blood collection (CBC, electrolytes and/or VBG, liver function tests, kidney 
function tests) 
o Urine collection (same as section 6.1) 
• Medication adherence questionnaire (appendix E): family to send this to us electronically 
or via mail. 
• Interview elements 
o AE assessment 
o Concomitant medication review 
o Ongoing therapies (same as section 6.1) 
• Dose Adjustment (see section 5.2) – After venous blood gas and electrolytes have resulted, 
partnering clinician will instruct patient/caregiver regarding administration of drug or 
placebo via phone call, telehealth, or in person. 


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6.3 
Visit 3 (Remote)– Week 3-5 
• Procedural elements 
o Blood collection (same as section 6.2) 
o Urine collection (same as section 6.1) 
• Medication adherence questionnaire (appendix E): family to send this to us electronically 
or via mail. 
• Interview elements 
o AE assessment 
o Concomitant medication review 
o Ongoing therapies (same as section 6.1) 
• Dose Adjustment (see section 5.2) – After venous blood gas and electrolytes have resulted, 
partnering clinician will instruct patient/caregiver regarding administration of drug or 
placebo via phone call, telehealth, or in person. 
6.4 
Visit 4 (Remote)– Visit 3 +1-3 weeks 
• Procedural elements 
o Blood collection (same as section 6.2)  
o Medication adherence questionnaire (appendix E): family to send this to us 
electronically or via mail. 
• Interview elements 
o AE assessment 
o Concomitant medication review 
o Ongoing therapies (same as section 6.1) 
• Dose Adjustment (see section 5.2) – After venous blood gas and electrolytes have resulted, 
partnering clinician will instruct patient/caregiver regarding administration of drug or 
placebo via phone call, telehealth, or in person. At this visit, the dose can only be adjusted 
downwards. If the dose needs to be adjusted, repeat CBC, electrolytes and/or VBG will be 
checked within 4 weeks of the dose adjustment. Repeat downward dose adjustments based 
on labs and repeat CBC + VBG or electrolytes will occur until either the dose does not 
need to be adjusted downwards or the subject is off therapy. 
6.5 
Visit 5 – Week 21-34 
• Interview elements: 
o Concomitant medication review 
o Ongoing therapies (same as section 6.1)  
o Medication adherence questionnaire (see section 6.2) 
o AE assessment 
• Procedural elements: 
o Physical exam (see section 6.1) 
o Mini-ICARS  
o PATA 
o NPCRS 
o Blood collection (see section 6.1) In addition, random blood level of acetazolamide 
will be collected.  


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o Urine collection (see section 6.1)  
• Survey given to families to complete and returned to site at or after visit by mail or 
electronically 
o PROMIS 
• Open Label Extension (OLE) or discontinuation – investigator will discuss with family 
option of rolling over into an open label extension of the study where the patient will 
receive the drug. If patient/caregivers decide to proceed with OLE, the patient will be 
started on dose 1 of acetazolamide. 
 
6.6 
Visit 6 (Remote)– Visit 5 +1-3 weeks 
• Procedural elements 
o Blood collection (same as section 6.2) 
o Urine collection (same as section 6.1) 
• *Medication adherence questionnaire (see section 6.2) 
• Interview elements 
o AE assessment 
o Concomitant medication review 
o Ongoing therapies (same as section 6.1) 
• *Dose Adjustment (see section 5.2) – After venous blood gas and electrolytes have 
resulted, investigator will instruct patient/caregiver regarding administration of drug via 
phone call, telehealth, or in person. 
* Will only be performed for those individuals who opted to continue in the OLE. 
6.7 
Visit 7 (Remote)– Visit 6 + 1-3 weeks 
• Procedural elements 
o Blood collection (same as section 6.2) 
o Urine collection (same as section 6.1) 
• *Medication adherence questionnaire (see section 6.2) 
• Interview elements 
o AE assessment 
o Concomitant medication review 
o Ongoing therapies (same as section 6.1) 
• *Dose Adjustment (see section 5.2) – After venous blood gas and electrolytes have 
resulted, investigator will instruct patient/caregiver regarding administration of drug via 
phone call, telehealth, or in person. 
* Will only be performed for those individuals who opted to continue in the OLE. 
 
6.8 
Visit 8 (Remote)– Visit 7 +1-3 weeks 
• Procedural elements 
o Blood collection (same as section 6.2)  
o *Medication adherence questionnaire (appendix E): family to send this to us 
electronically or via mail. 


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• Interview elements 
o AE assessment 
o Concomitant medication review 
o Ongoing therapies (same as section 6.1) 
• *Dose Adjustment (see section 5.2) – After venous blood gas and electrolytes have 
resulted, partnering clinician will instruct patient/caregiver regarding administration of 
drug or placebo via phone call, telehealth, or in person. At this visit, the dose can only be 
adjusted downwards. If the dose needs to be adjusted, repeat CBC, electrolytes and/or VBG 
will be checked within 4 weeks of the dose adjustment. Repeat downward dose adjustments 
based on labs and repeat CBC + VBG or electrolytes will occur until either the dose does 
not need to be adjusted downwards or the subject is off therapy. 
* Will only be performed for those individuals who opted to continue in the OLE. 
 
6.9 
Visit 9 – Week 49-105 
• Interview elements: 
o Concomitant medication review 
o Ongoing therapies (see section 6.1) 
o *Medication adherence questionnaire (see section 6.2) 
o AE assessment 
o Reason for discontinuation of study treatment and discontinuation of study 
• Procedural elements: 
o Physical exam (see section 6.1)  
o Mini-ICARS  
o PATA 
o NPCRS 
o Blood collection (see section 6.1)  
o Urine collection (see section 6.1)  
o Annual screening ophthalmological exam including intraocular pressure testing. 
• Survey given to families to complete and returned to site at or after visit by mail or 
electronically 
o PROMIS 
6.10 Visit – Early Termination 
• Procedural elements 
o Blood collection (same as section 6.1) 
o Urine collection (same as section 6.1) 
• Medication adherence questionnaire (see section 6.2) 
• Interview elements 
o AE assessment 
o Concomitant medication review 
o Ongoing therapies (same as section 6.1) 
o Reason for discontinuation of study treatment and discontinuation of study 


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• Study withdrawal – investigator will discuss with the patient and caretakers the reason for 
withdrawal from the study. Investigator will also attempt to consent/assent subject and/or 
caretaker family to collect follow up information whenever possible through review of 
medical records. Data to be collected include lab data to look at urinalysis values, 
chemistries in serum, hematology, physical exam data (including vital signs and reviewing 
concomitant medications), ICARS scoring, NPCRS scoring and any other adverse events 
if available. These evaluations will be obtained as part of their clinical care. 
 


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Table 3: Schedule of Events 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Early 
(Wk 0) 
(Wk 2-3) 
(Wk 3-5) 
(Visit 3 +  
1-3 wks) 
(Wk 21-34) 
(Visit 5 +  
1-3 wks) 
(Visit 6 + 
1-3 wks) 
(Visit 7 +  
1-3 wks) 
(Wk 49-
105) 
Withdrawal 
Informed Consent 
x 
Medical History 
x 
Clinical History 
x 
Physical Exam* 
x 
 
x 
 
x 
 
HC 
x 
x 
x 
x 
x 
 
Height 
x 
x 
x 
x 
x 
 
Weight 
x 
x 
x 
x 
x 
 
Vital Signs (Temperature, BP, 
RR, HR) 
x 
 
x 
 
x 
 
Ophthalmological exam including 
intraocular pressure testing** 
 
 
 
 
x 
 
NPCRSa 
x 
 
x 
 
x 
 
Mini-ICARSb 
x 
 
x 
 
x 
 
PATA 
x 
 
x 
 
x 
 
Bloodc collection 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urined Collection 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
PROMISe 
x 
 
x 
 
x 
 
I/E review; Randomization 
x 
Dose Initiation 
x 
Dose Adjustment 
x 
x 
x 
x 
x 
x 
x 
 
Open label continuation or 
discontinuation 
 
x 
 
 
x 
Medication adherence questionnaire 
x 
x 
x 
x 
x 
x 
x 
x 
x 
AE Assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant Medication Review 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Ongoing therapies (PT, OT, ST, FT)f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
aAppendix A bAppendix B cBlood labs: see sections 6.1 and 6.2 dUrine labs: see section 6.1. ePROMIS: Subset of patient reported outcomes as for natural history trial based on 
PROMIS questionnaire. See Appendix C. fPT = physical therapy, OT = occupational therapy, ST = speech therapy, FT = feeding therapy – collecting information regarding if 
Table 3: Schedule of Events 


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therapy ongoing (yes/no), number sessions per month. Grey shading: only for subjects who continue in OLE.*head circumference, height, and weight will be measured at least 
every 12 weeks. **to be done offsite as part of routine clinical care. 
Abbreviations: Wk = week, I/E inclusion and exclusion criteria, HC = head circumference, BP = blood pressure, RR = respiratory rate, HR = heart rate 


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7 Statistical Plan 
7.1 
Sample Size Determination 
Given that the improvement in ICARS, which is highly correlated to the Mini-ICARS, was 5.6 
points over roughly 20 months (Serrano, 2015), if we assume a linear change, then we have 
5.6*(6/20) = 1.68 points decrease over 6 months. The expected effect size in the experimental 
group is 6 points decrease, whereas it is 1.68 in the placebo.  Using a standard deviation of the 
change in scores of 4, two-sided alpha 0.05, and power 75%, the sample size required to detect a 
true difference of 4.32 units is 26 patients total (13 per arm) based on the two-sample t-test. 
7.2 
Statistical Methods 
Descriptive Statistics 
Univariate descriptive statistics and frequency distributions will be calculated, as appropriate for 
all variables.  Baseline values for demographic, clinical, and outcome variables (primary and 
secondary) will be tabulated for the treatment groups.  These analyses will help identify potential 
confounding variables to be used as covariates in sensitivity analyses.  Distributions across 
subgroups used in randomization will be qualitatively compared to assess whether the 
randomization was successful in equalizing distributions of these prognostic variables across 
treatment groups.  Putative prognostic variables that will be investigated through these 
descriptive analyses include variables such as sex, baseline Mini-ICARS score, age, and baseline 
NPCRS score. 
 
Primary Endpoint Analysis Approach:  
Primary Hypothesis: The administration of acetazolamide will improve the ataxia symptoms in 
patients with PMM2-CDG. Primary Endpoint: Change in Mini-ICARS score from baseline to 
6 months. 
The primary analysis will be conducted using the full analysis set (see Section 7.3). The 
between-arm mean difference in the change in Mini-ICARS score from baseline to 6 months will 
be evaluated via a two-sample t-test. The primary analysis will include all patients with a 
baseline and 6-month Mini-ICARS score. As a sensitivity analysis, all patients with a missing 
Mini-ICARS score at 6 months will be assumed to have no change in Mini-ICARS score 
between baseline and 6 months.  A per-protocol analysis will also be conducted using the per-
protocol set (see Section 7.3).  A nominal significance level of α=0.05 will be used for all 
analyses. 
Exploratory Analysis: To explore characteristics of individuals with PMM2-CDG who do not 
respond to acetazolamide (objective 4), we will define the subgroup of individuals who received 
at least 6 months of acetazolamide and did not have an improvement in ataxia. These individuals 
could have received acetazolamide during either the blinded period or open label extension 
period for at least 6 months. In addition, their Mini-ICARS score difference after being on 
acetazolamide for at least six months was at or less than the mean Mini-ICARS score change for 
the placebo group. A correlation analysis for change in Mini-ICARS from baseline to 6 months 
will be performed with each of the baseline characteristics. These baseline characteristics include 
age, sex, weight, height, head circumference, NPCRS score, Mini-ICARS score, PATA score, 
concomitant medication list, allergies, current ability with activities of daily living, laboratory 


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data (carbohydrate deficient transferrin results (Mono/Di, A/Di, Apo CIII1/Apo C III2, Apo 
CIII0/Apo CIII2), electrolytes (Na, K, Cl, CO2), VBG (pH, pCO2, PO2, CO2, Base excess) or 
bicarbonate/CO2, 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), ongoing therapies 
(physical, occupation, speech therapy yes/no and sessions/month), physical exam elements 
(normal/abnormal for each examined system including neurologic exam, cardiovascular exam, 
abdominal exam, HEENT exam, dermatologic exam, pulmonary exam), prior or existing medical 
conditions within the standard body systems (present/absent – general, dermatologic, HEENT, 
cardiovascular, respiratory, GI, GU, musculoskeletal, neurologic, allergic, immunologic, 
hematologic, endocrine), and number of past hospitalizations. 
 
Secondary Endpoint Analysis Approach:  
Secondary Endpoint 1: Incidence of (a) drug related adverse event(s) and (b) drug related 
serious adverse event(s) while they are on blinded therapy. The maximum grade for each type of 
adverse event will be summarized using the CTCAE v5.0. Using the safety set (see Section 7.3), 
the frequency and percentage of patients with a grade 1+ adverse event or serious adverse event 
classified as possibly, probably, or definitely related to the study treatment will be summarized 
by treatment arm. The frequency and percentage of patients who discontinue study treatment due 
to adverse events will also be reported by treatment arm. This analysis will be repeated to 
evaluate incidence of (a) drug related adverse event(s) and (b) drug related serious adverse 
event(s) for the duration that patients remain in the open label extension. 
Secondary Endpoint 2: PMM2-Biomarker and other scores including:  
• carbohydrate deficient transferrin results (Mono/Di, A/Di, Apo CIII1/Apo C III2, Apo 
CIII0/Apo CIII2),  
• electrolytes (Na, K, Cl, CO2),  
• VBG (pH, pCO2, PO2, CO2, Base excess) or bicarbonate/CO2,  
• 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,  
• the PATA score,  
• and NPCRS score.  
As these endpoints are all numeric, and to identify if the post blinded therapy or final 
measurement of the open label extension is different from the baseline value, we will use a linear 
regression model to test if there is a change from baseline. Using the full analysis set (see Section 
7.3), the between-arm mean difference in 6-month scores will be evaluated via a linear 
regression model predicting 6-month scores from baseline scores and treatment arm. This 
analysis will be repeated based on the final measurement of the open label extension. A nominal 
significance level of α=0.05 will be used for all analyses. 
 


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Handling of Intercurrent Events 
Per the E9(R1) guidance (Statistical Principles for Clinical Trials; Addendum: Estimands and 
Sensitivity Analysis in Clinical Trials), a treatment policy strategy will be used to address 
intercurrent events. That is, for the primary analysis, each patient’s change in Mini-ICARS score 
from baseline to 6 months will be used regardless of whether an intercurrent event occurs. 
 
Handling of Missing Data 
Attempts to minimize missing data will be made through site training and data monitoring (e.g., 
form delinquency notifications, data queries). Patients who prematurely discontinue study 
treatment will be encouraged to remain in the study for their scheduled efficacy and safety 
assessments. The primary analysis evaluating the between-arm mean difference in the change in 
Mini-ICARS score from baseline to 6 months will include all patients with a baseline and 6-
month Mini-ICARS score. For patients with a missing Mini-ICARS score at 6 months, 
imputation will be used as part of a sensitivity analysis. Specifically, all patients with a missing 
Mini-ICARS score at 6 months will be assumed to have no change in Mini-ICARS score from 
baseline to 6 months (i.e., 0 imputed for all missing change scores). 
 
Multiplicity 
No adjustment for multiplicity will be made, though interpretation will take into consideration 
that the type I error is strictly controlled for the primary endpoint only.  Overall interpretation 
will also take into consideration consistency of results across analyses. 
 
Interim Analysis 
No interim analysis will be conducted. 
7.3 
Subject Populations for Analysis 
• Intent-to-treat set: All randomized patients, regardless of whether they received their 
assigned study treatment. 
• Full analysis set: All randomized patients who complete the baseline and 6-month visits. 
• Safety set: All randomized patients who receive at least one dose of acetazolamide or 
placebo. 
• Per-protocol set: All randomized patients who report taking at least 4 weeks of their 
assigned study treatment and complete the baseline and 6-month visits. 
8 Safety and Adverse Events 
Blood will be collected at regular intervals to assess electrolytes level, kidney function, 
coagulation factor, and measure of base. Urine will also be collected at regular intervals to assess 
calcium and protein levels. Routine urinalysis will also be performed to monitor for any 
significant changes in body fluids as a result of acetazolamide function. Monitoring for 
thrombocytopenia, electrolyte disturbances, and metabolic acidosis should be completed within 4 
weeks of a dose increase. If significant changes occur in blood or urine tests, risk will be re-
evaluated by the principal investigator to determine if acetazolamide should be continued as per 
below. The AE reporting period will encompass visits 0 to 9 of the study. If a subject withdraws 
early, we will attempt to assess AEs up to 91 weeks after enrollment through review of medical 
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8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, DSMB reports, interim findings, product labeling change) that in the opinion 
of the local investigator may adversely affect the rights, safety, or welfare of the subjects 
or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
acetazolamide package insert, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) or placebo in a patient or research subject. AEs may also be problems/events 
that in the opinion of the investigator may have adversely affected the rights, safety, or welfare 
of the subjects or others, or substantially compromised the research data. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include; 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant disability or incapacity 
• birth defect/anomaly 
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period 
 
The study site will document all AEs that occur (whether or not related to study drug) within one 
week of the investigator becoming aware of the event. The collection period for all AEs will 
begin after informed consent is obtained and end after procedures for the final study visit have 


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been completed. In accordance with the standard operating procedures and policies of the local 
Institutional Review Board (IRB), the site investigator will report SAEs to the IRB.   
 
Pre-existing Condition 
A pre-existing condition is one that is present at the start of the study.  A pre-existing condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition.  At the end of the study, any new or worsening clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be documented and 
reported as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report, to the investigator, any 
subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if they meet the 
following criteria: 
• Hepatic impairment defined as AST/ALT >3.0 - 5.0 x ULN if baseline was normal; >3.0 
- 5.0 x baseline if baseline was abnormal 
• Renal impairment defined as serum creatinine 1.5-1.9 times ULN for age OR ≥ 26.5 umol/l 
increase from ULN for age 
 
If these values are noted and no other cause for these laboratory changes are likely, then drug 
will be stopped, and repeat labs will be obtained at reasonable intervals per investigator’s clinical 
judgement after discontinuation until labs have normalized to stabilized. Treatment may be 
restarted if labs have returned to baseline using the same ramp up schedule as described for visits 
2, 3 and 4. These changes in treatment will be documented. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances:  
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 


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event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
8.2 
Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in a separate adverse event 
worksheet.  All clearly related signs, symptoms, and abnormal diagnostic, laboratory or 
procedure results should be recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study treatment or participation is not the probable cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up to determine the 
final outcome. Any serious adverse event that occurs during the Adverse Event Reporting Period 
and is considered to be at least possibly related to the study treatment or study participation 
should be recorded and reported immediately. 
 
The most up to date National Cancer Institute’s Common Terminology Criteria for Adverse 
Events (CTCAE) should be used to assess and grade AE severity, including laboratory 
abnormalities judged to be clinically significant. The modified criteria can be found in the study 
manual (appendix D).  If the experience is not covered in the modified criteria, the guidelines 
shown in Table  below should be used to grade severity.  It should be pointed out that the term 
“severe” is a measure of intensity and that a severe AE is not necessarily serious. 
Table 4.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 


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AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the guidelines 
in Table . 
Table 5.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriate action necessary 
to protect the study subject and then complete the Study Adverse Event Worksheet and log.  The 
investigator will evaluate the event and determine the necessary follow-up and reporting 
required. 
 
8.3.1 Investigator reporting: notifying the IRB 
 
The investigator will report to the IRB any UPIRTSOs and Non-UPIRTSOs according to the 
IRB Policy and Procedures. 
 
Information collected on the adverse event worksheet: 
• Subject’s name:  
• Medical record number:  
• Disease/histology (if applicable):  
• The date the adverse event occurred:  
• Description of the adverse event:  
• Relationship of the adverse event to the research (drug, procedure, or intervention):  
• If the adverse event was expected:  


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• The severity of the adverse event: (use a table to define severity scale 1-5) 
• If any intervention was necessary:  
• Resolution: (was the incident resolved spontaneously, or after discontinuing treatment) 
• Date of Resolution:  
 
The investigator will review all adverse event reports to determine if specific reports need to be 
made to the IRB.  The investigator will sign and date the adverse event report when it is 
reviewed.  For this protocol, only directly related SAEs/UPIRTSOs will be reported to the IRB. 
 
8.3.2 
Investigator reporting: Notifying the FDA 
The sponsor-investigator will report to the FDA all unexpected, serious suspected adverse 
reactions according to the required IND Safety Reporting timelines, formats and requirements. 
 
Unexpected fatal or life threatening suspected adverse reactions where there is evidence to 
suggest a causal relationship between the study drug/placebo and the adverse event, will be 
reported as a serious suspected adverse reaction.  This will be reported to the FDA on FDA Form 
3500A, no later than 7 calendar days after the sponsor-investigator’s initial receipt of the 
information about the event. 
 
Other unexpected serious suspected adverse reactions where there is evidence to suggest a causal 
relationship between the study drug/placebo and the adverse event, will be reported as a serious 
suspected adverse reaction.  This will be reported to the FDA on FDA Form 3500A, no later than 
15 calendar days after the sponsor-investigator’s initial receipt of the information about the 
event. 
 
Any clinically important increase in the rate of serious suspected adverse reactions over those 
listed in the protocol or product insert will be reported as a serious suspected adverse reaction.  
This will be reported to the FDA on FDA Form 3500A no later than 15 calendar days after the 
sponsor-investigator’s initial receipt of the information about the event. 
 
The sponsor-investigator must also notify the FDA (and sponsors must notify all participating 
investigators) in an IND safety report of potential serious risks, from clinical trials or any other 
source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines 
that the information qualifies for reporting under § 312.32(c)(1)(i)-(iv). 
 
Findings from other studies in human or animals that suggest a significant risk in humans exposed 
to the drug will be reported.  This will be reported to the FDA on FDA Form 3500A, no later than 
15 calendar days after the sponsor-investigators initial receipt of the information about the event. 
 
8.4 
Unmasking/Unblinding Procedures 
 
In the event that a subject needs to be unblinded for safety reasons, a member of the study team 
will contact the research pharmacy to learn the treatment the subject is on in order to provide 


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necessary care. If a subject needs to be unblinded for safety reasons, this may be documented in 
the subject’s file, and may need to be documented as an SAE. Regardless of if the event is 
classified as an SAE or not, the event will be reported within 1 week of learning about the event. 
Each study site’s PI will be responsible for reporting the unblinding and SAE to the IRB and 
DSMB for the subjects enrolled at their site. They will also notify the lead investigator of the 
SAE as well as the DSMB. 
8.5 
Stopping Rules  
Any SAEs greater than grade 3 (severe) as defined as “marked limitation in activity, medical 
intervention/therapy required, hospitalizations possible” will qualify as study stoppage for the 
rest of the study. The central Data and Safety Monitoring Board (DSMB) will be notified and 
they will determine if the study would need to be placed on hold with IRB. The study may be 
restarted if the SAE resolves or is deemed unrelated to the study.  
 
Additionally, if clinical laboratory results show: 
• 
Hepatic impairment defined as AST/ALT >3.0 - 5.0 x ULN if baseline was normal; >3.0 
- 5.0 x baseline if baseline was abnormal 
• 
Renal impairment defined as serum creatinine 1.5-1.9 times ULN for age OR ≥ 26.5 umol/l 
increase from ULN for age  
 
If no other cause for these laboratory changes are likely, then drug will be stopped, and repeat 
labs will be obtained at reasonable intervals per investigator’s clinical judgement after 
discontinuation until labs have normalized to stabilized. Treatment may be restarted if labs have 
returned to baseline using the same ramp up schedule as described for visit 2 and 3. The DSMB 
will also be notified. 
8.6 
Medical Monitoring 
It is the responsibility of the Investigator at each site to oversee the safety of the study at his/her 
site. Any SAE will be reported to the DSMB, which will make decisions regarding unblinding. 
This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 10 “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
8.6.1 Independent Data and Safety Monitoring Board 
Data Safety Monitoring Board (DSMB) will be headed by a biochemical geneticist from an 
outside hospital.  Other members include a neurologist and biochemical geneticist at SCH, and a 
member of the UW ITHS. Our study biostatistician will provide statistical support when needed. 
The DSMB will review data mainly relating to safety. There will be a pre-study review and 
interim reviews every year conducted by the DSMB for the purpose of monitoring study conduct 
and assessing individual safety. All eligible individuals who are randomized into the study and 
receive at least one dose of the study drug (the Safety Population) will be included in the safety 
analysis. 


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9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status that 
the subject is alive) at the end of their scheduled study period. 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
9.3 
Case Report Forms 
 
The electronic study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All missing data must be explained.  
Reasons for missed visits should be collected when possible and documented.  Within REDCap, 
a CRF should not be marked as “Complete” until all fields are completed or are intentionally left 
blank (e.g., due to a procedure or questionnaire not being completed during the acceptable time 
window). 
 
Data Management 
 
Data collection is the responsibility of the study staff at the site under the supervision of the site 
Primary Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of data. 


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The DMCC will develop, test, and maintain the data capture system using a web-based data 
collection system, REDCap, as the primary source of data entry and storage. REDCap is a software 
toolset and workflow methodology for electronic collection and management of research and 
clinical trial data developed by Vanderbilt University, with collaboration from a consortium of 
institutional partners including the University of Cincinnati Academic Health Center. The 
REDCap system provides a secure, web-based application that is flexible and provides: 1) an 
intuitive interface for users to enter data and have real time validation rules (with automated data 
type and range checks) at the time of entry; 2) HIPAA-compliant and 21 CFR Part 11-ready audit 
trails for tracking page views, data manipulation and export procedures; 3) record locking and 
electronic signature functions; 4) fine grained control of user rights to view and manipulate data, 
and tool to sequester data access for multiple sites; 5) a report builder for reporting, monitoring 
and querying patient records; and 6) automated export procedures for seamless data downloads to 
common statistical packages (SPSS, SAS, Stata, R/S-Plus). 
Study data will be entered into REDCap, supported by the DMCC. The REDCap system complies 
with all applicable guidelines to ensure patient confidentiality, data integrity, and reliability. All 
data management best practices including quality controls and data validation procedures will be 
applied to ensure the validity and accuracy of the clinical database. A data management plan will 
be developed which will describe the data collection process, database development, quality 
control processes and reporting. 
 
Data Processing 
 
Data will be entered into the eCRF by single entry at each participating site by the study 
coordinator or investigator within 3 business days of data collection.   
 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials.   
 
Data Security and Confidentiality 
 
All subjects enrolled into this study will be assigned a unique numerical identifier. The code 
linking this study number to the identifiable patient will be kept secure behind the Mayo Clinic 
firewall on password protected drives only accessible by essential study staff. The linking will 
also be maintained securely at each local site. All other records will also be kept in this fashion. 
Hard copy records will be maintained in binders housed in staff only areas and will be locked 
behind doors and/or desks as able.  
 
We will use a system of coded identifiers to protect subject confidentiality and safety.  Each 
subject enrolled will be assigned a local identifier by the enrollment site.  This number can be a 
combination of the site identifier (location code) and a serial accession number.  Only the 
enrolling site will have access to the linkage between this number and the personal identifier of 
the subject.  When the subject is enrolled in the study, a web-based system will be used to 


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generate another subject ID number (e.g. Globally Unique Identifier or GUID).  Thus, each 
subject will have two codes: the local one that can be used by the enrolling site to obtain personal 
identifiers and a second code assigned by the web-based system.  For all data transfers to the 
DMCC both numbers will be required to uniquely identify the subject.  Using this methodology, 
it is possible to protect against data keying errors, digit transposition or other mistakes when 
identifying a subject for data entry since the numbers should match to properly identify the 
subject.   
 
Data Quality Assurance 
 
The initial data entry will take place by a single member of the study team. An additional study 
team member may verify that this data matches the medical record and/or CRFs.  
 
Data Clarification Process 
 
After data have been entered into the study database, a system of computerized data validation 
checks will use normative data ranges for first line queries.  These automatic queries can be 
corrected by the study coordinator at the time of data entry. The DMCC will issue additional 
queries which should be addressed by the study team within 10 days before a second query is 
generated.  All queries will be tracked and resolved through the EDC system. 
9.4 
Records Retention 
 
The investigator will maintain records and essential documents related to the conduct of the 
study.  These will include subject case histories and regulatory documents. 
 
Subject names and other identifiable information will not be included on any reports, 
publications, or other disclosures of clinical study outcomes.  
 
The investigator will retain the specified records and reports for; 
1. Until 2 years after shipment and delivery of the drug for investigational use is 
discontinued OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy”
   
whichever is longer. 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The investigator at each local site will allocate adequate time for such monitoring activities.  The 
Investigator at each local site will also ensure that the monitor or other compliance or quality 
assurance reviewer is given access to all the study-related documents and study related facilities 


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(e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the monitoring 
visit. 
10.1.1 Study synopsis 
A synopsis of the study is provided in the Study Summary and is greater than minimal risk. The 
proposed participating clinical sites in which recruitment, consent, and study procedures will 
occur will be Seattle Children's Hospital, Mayo Clinic in Minnesota, and Children’s Hospital of 
Philadelphia.  
10.1.2 Roles and Responsibilities 
The investigators including the lead principal investigator, site principal investigators, and co-
investigators are responsible for monitoring the safety of the trial. All investigators are qualified 
providers with expertise in managing genetic conditions. The DSMB will also aid in 
determination of safety and if the trial needs to be paused or discontinued, or if the trial can 
resume (see section 8.6.1).  
10.1.3 Trial Safety 
See section 8 for description of any specific events that would preclude a subject from 
continuing the intervention and managing any medication related issues. See section 1.5 for 
potential risks and measures in place to protect subjects against foreseeable risks. Consent and 
assent procedures are described in section 11 below. Individuals will be consented or assented in 
person face to face. Subject privacy will be protected by the following measures - interviews will 
take place in a private room, testing data will be shared with subject’s legally authorized 
representative, privacy for minors, communication between investigators and subject will be 
performed via secure means including via secure telephone, web portal, telehealth software. Trial 
stopping rules are described in section 8.5. Incidental findings will be reported to the subject and 
their parent/legal guardian, or legally authorized representative as well as their clinical provider. 
Decisions regarding management of these incidental findings will be deferred to the subject’s 
clinical provider and family. Any conflicts of interest will be disclosed as per section 12.2. As a 
multi-center study, compliance with the monitoring plan will be ensured by the site PI, and data 
will be reported across study sites electronically. Additionally, all study related data will be 
collected in a centralized database as per section 9. Data security measures to protect the 
confidentiality of the data are also described in section 9. 
10.1.4 Reportable Events 
The process and timeline for reporting AEs, SAEs, and UPIRSO are described in section 8.3. 
10.1.5 Data Management, Analysis, and Quality Assurance 
Data sources include PROMIS questionnaire (paper or electronic, Appendix C), mini-ICARS 
scores – Appendix B and video recordings, medical records, and medication adherence 
questionnaire – Appendix E. These data sources will be stored in electronic records that will be 
password protected behind institutional firewalls labeled only with the subject ID and study ID. 
Physical data sources (i.e., paper questionnaires or records) will be stored in a secure area that is 
locked from the public that only the study team will be able to access. The DMCC will 
intermittently review the data of the demographics of subjects and randomization to ensure that 


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subject recruitment and enrollment are on target for the validity and integrity of the data. They 
will provide the investigators a report electronically (e-mail) regarding recruitment status once 
every 3 months. The trial will be performed, and the data will be generated, documented 
(recorded), and reported in compliance with Good Clinical Practice (GCP). 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, and 
government regulatory agencies, of all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data etc.).  The investigator will ensure 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
 
Self-monitoring of participant sites will be coordinated by the Mayo program coordinator. Self-
monitor forms will be sent to all participating sites on an annual basis. Each site will be 
responsible for reviewing study documentation, completing the forms, and returning them to the 
Mayo program coordinator, who will then review the forms, clarify any questions or concerns, 
and send a self-monitor acknowledgment letter to site PI and coordinator. Each site, as well as 
the IND sponsor, will retain self-monitor documentation and letters in their regulatory binders. 
 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the investigator before commencement of this study. 
 
All subjects with a developmental and actual age of  ≥18 years will be provided a consent form 
describing this study and providing sufficient information for subjects to make an informed 
decision about their participation in this study.  This consent form will be submitted with the 
protocol for review and approval by the IRB for the study.  The formal consent of a subject, 
using the Approved IRB consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject or the subject’s legally authorized 
representative, and the individual obtaining the informed consent.  
 
The PI or a designee will determine whether adult subjects are able to provide consent using both 
previous results from formal assessments of intellectual capacity (such as neuropsychological 
testing results) and/or determinations made based on conversations with the impaired adult at 
and before the time of consent. Some adult patients might not be able to give informed consent 
due to developmental disabilities. If patients’ developmental functioning level is less than 18 


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years of age, the patient will be classified as “unable to consent for self.” To assess an adult 
patient’s capacity to consent, we will use both previous formal assessments of intellectual 
capacity (such as neuropsychological testing results) as well as determinations made based on 
conversations with the impaired adult at and before the time of consent. We will obtain informed 
consent for intellectually impaired adults using their appointed surrogate decision-maker or 
another legally authorized representative (LAR), such as a person who has a legal guardian or for 
whom a durable power of attorney (DPA) has been granted. An appropriate LAR is one who at 
least: 1) understands that the protocol involves research; 2) understands the risks, potential 
benefits (if any), and alternatives to the study; and 3) has sufficient reason to believe 
participation in the study is consistent with the subject's preferences and values. When subjects 
are judged to have mental competence above that of a 7-year-old, the team will use the assent 
process (when possible and appropriate) in addition to obtaining informed consent via a LAR. 
 
Our study will involve greater than minimal risk on children as a study drug is being 
administered. However, the risk is justified by the prospect of direct benefit to the individual 
subject, the relation of the anticipated benefit to the risk is favorable to the subject as compared 
to the lack of available alternative therapeutic approaches in PMM2-CDG; and adequate 
provisions will be made for soliciting the permission of their parents or legal guardians or legally 
authorized representative. A legal guardian is an individual who is authorized under applicable 
state or local law to consent on behalf of a child to (a) general medical care when general 
medical care includes participation in research; or (b) to participate in research [DHHS 45 CFR 
§46.402(e); FDA 21 CFR 50.3(s)]. A legally authorized representative is an individual, judicial, 
or other body authorized under applicable law (e.g., a person appointed as a health agent, a court-
appointed legal guardian of the person, as well as next-of-kin) to consent or otherwise provide 
permission on behalf of a subject, either prospectively or during the course of research, to the 
subject's participation in the procedure(s) involved in the research. [DHHS 45 CFR §46.102(c); 
FDA 21 CFR §50.3(l)]. 
 
An assent form will be used in children that are capable of providing assent. This same assent 
form will also be used for selected intellectually impaired adults with sufficient comprehension. 
Consent for children will be obtained from a parent/legal guardian.  
 
Minors will be asked to complete an adult research consent form when they reach 18 years of 
age if not developmentally disabled as noted above. If they do not complete the adult research 
consent form, they will be classified as a partial withdrawal. The research team/registry will keep 
their specimens, and scientists will have access to their specimens and study data (e.g. answers to 
health surveys), however, we will not recontact them and their name and contact information will 
not be released to researchers for recruitment into follow-up studies. 
 
Subjects will be free to voluntarily withdraw from participation at any time. To minimize drop-
out or loss to follow up, subjects will be contacted at least once a year by the study coordinator. 
At that time contact information will be verified and major changes in disease evolution or 
treatment will be noted, along with significant health issues. 
 


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12 Study Finances 
12.1 Funding Source 
This study is funded by the FCDGC (Frontiers of Congenital Disorders of Glycosylation 
Consortium). The FCDGC is funded through a U54 NIH Grant. External funding through 
institution-based organizations may also be sought prospectively. 
12.2 Conflict of Interest 
Any study team member who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) must 
have the conflict reviewed by a properly constituted Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
study investigator prior to participation in this study.  
13 Publication Plan 
The principal investigator and site principal investigators and co-investigators will be responsible 
for the publication of the results of this study. Approval from the principal investigator must be 
obtained before any information can be used or passed on to a third party. The study will be 
registered to ClinicalTrials.gov (https://register.clinicaltrials.gov/) prior to subject recruitment 
and enrollment, and results will be posted to ClinicalTrials.gov within 12 months of final data 
collection for the primary outcome.   
14 References 
Acetazolamide. (2020). In Physicians’ Desk Reference. Retrieved from https://www.pdr.net/drug-
summary/Acetazolamide-Tablets-acetazolamide-667. 
 
Bain PG, O’Brien MD, Keevil SF, et al. Familial periodic cerebellar ataxia: a problem of 
cerebellar intracellular pH homeostasis. Ann Neurol 1992;31:147–154. 
 
Barone R, Fiumara A, Jaeken J. Congenital disorders of glycosylation with emphasis on 
cerebellar involvement. Semin Neurol 2014;34:357–366. 
 
Barone R, Carrozzi M, Parini R, et al. A nationwide survey of PMM2-CDG in Italy: high 
frequency of a mild neurological variant associated with the L32R mutation. J Neurol 
2015;262:154–164. 
 
De Diego V, Martínez-Monseny AF, Muchart J, et al. Longitudinal volumetric and 2D 
assessment of cerebellar atrophy in a large cohort of children with phosphomannomutase 
deficiency (PMM2-CDG). J Inherit Metab Dis 2017;40:709–713. 
 
Distelmaier F, Sengler U, Messing-Juenger M, et al. Pseudotumor cerebri as an important differential 
diagnosis of papilledema in children. Brain and Development. 2006;28:190-195. [PubMed 16368210] 
 
Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurology of inherited glycosylation disorders. 
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Grünewald S, Matthijs G, Jaeken J. Congenital disorders of glycosylation: a review. Pediatr Res 
2002;52:618–624. 
 
Grünewald S. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim 
Biophys Acta 2009;9:827-34. 
 
Hacifazlioglu N, Yilmaz Y. Pseudotumour cerebri in children: etiological, clinical features and treatment 
modalities. European Journal of Paediatric Neurology. 2012;12:349-355. [PubMed 22050895] 
 
Izquierdo-Serra M, Martínez-Monseny AF, López L, et al. Strokelike episodes and cerebellar 
syndrome in phosphomannomutase deficiency (PMM2-CDG): evidence for 
hypoglycosylation-driven channelopathy. Int J Mol Sci 2018;19. pii: E619. 
 
Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P et al. Familial psychomotor retardation 
with markedly fluctuating serum proteins, FSH and GH levels, partial TBG-deficiency, 
increased serum arylsulphatase A and increased CSF protein: a new syndrome? Pediatr 
Res 1980;14:179. 
 
Jaeken J, Lefeber D, Matthjs G. Clinical utility gene card for: phosphomannomutase 2 
deficiency. Eur J Hum Genet Epub 2014; do i: 10.1038/ejhg. 2013.298. 
 
Ko MW,Liu GT. Pediatric idiopathic intracranial hypertension (Pseudotumor cerebri). Horm Res 
Paediatr. 2010;74:381-389. [PubMed 20962512] 
 
Martínez-Monseny AF, Bolasell M, Callejón-Póo L, et al. AZATAX: Acetazolamide safety and 
efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2-CDG). 
Ann Neurol 2019;85(5):740-751. 
 
Moffett BS, Moffett TI, Dickerson HA. Acetazolamide therapy for hypochloremic metabolic alkalosis in 
pediatric patients with heart disease. Am J Ther. 2007;14(4):331-335. [PubMed 17667206 ] 
 
Park, MK. Park's Pediatric Cardiology for Practitioners. 6th ed. Philadelphia, PA: Elsevier Health 
Sciences; 2014. 
 
Per H, Canpolat M, Gumus H, et al. Clinical spectrum of the pseudotumor cerebri in children: etiological, 
clinical features, treatment and prognosis. Brain Dev. 2013;35:561-568. [PubMed 22981259] 
 
Rangwala LM, Liu GT. Pediatric idiopathic intracranial hypertension. Survey of Ophthalmology. 
2007;52(6):597-617. [PubMed 18029269] 
 
Reiss WG and Oles KS, “Acetazolamide in the Treatment of Seizures,” Ann Pharmacother, 1996, 
30(5):514-9. [PubMed 8740334] 
 
Sappey-Marinier D, Vighetto A, Peyron R, et al. Phosphorus and proton magnetic resonance 
spectroscopy in episodic ataxia type 2. Ann Neurol 1999;46:256–259. 
 
Serrano M, de Diego V, Muchart J, et al. Phosphomannomutase deficiency (PMM2-CDG): 
ataxia and cerebellar assessment. Orphanet J Rare Dis 2015;10:138. 
 


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Serrano NL, de Diego V, Cuadras D, et al. A quantitative assessment of the evolution of 
cerebellar syndrome in children with phosphomannomutase-deficiency (PMM2-CDG).Orphanet J Rare 
Dis 2017;12:155. 
 
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15 Attachments 
Please see attached appendices. 
Appendix A: Nijmegen Pediatric CDG Rating Scale (NPCRS) 
Appendix B: mini-International Cooperative Ataxia Rating Scale (mini-ICARS) 
Appendix C: Patient-Reported Outcome Measurement Information System (PROMIS) 
Appendix D: Common Terminology Criteria for Adverse Events version 5 (CTCAE v5) 
Appendix E: Medication adherence questionnaire