Clinical trial: Metformin in Patients With Fragile X (NCT04141163)

Eligibility criteria:
Inclusion Criteria:

          -  Male between the ages of 16-50 years old at the time of consent

          -  Diagnosis of full mutation FXS.

          -  Stable on any psychoactive medication for at least 4 weeks before receiving study
             drug, including antidepressants, stimulants, antipsychotics, and mood stabilizers.

          -  Seizure free for at least the past 3 months.

          -  No major health issues or diseases expected to interfere with the study

          -  No history of diabetes

          -  Not currently taking metformin at the time of enrollment

          -  Average basal blood glucose HgbA1c < 7.0

          -  Study partner with frequent contact with patient willing to accompany patient to
             visits and complete caretaker/partner study forms

          -  No contraindication to metformin

          -  Willing to complete all baseline assessments and study procedures

        Exclusion Criteria:

          -  Has a medical condition that would make treatment unsafe such as diabetes, pancreatic
             disease, liver or kidney disease, a history of epilepsy or seizure disorder that is
             not controlled, as well as any other medical condition as determined by the study
             doctor.

          -  Has an eating disorder that has been clinically diagnosed, predisposing them to low
             BMI.

          -  Has received any investigational compound within 30 days prior to the first dose of
             study medication.

          -  Has received metformin in a previous clinical study or as a therapeutic agent.

          -  Is an immediate family member, study site employee, or in a dependent relationship
             with a study site employee who is involved in the conduct of this study (e.g., spouse,
             parent, child, sibling), or may consent under duress.

          -  Has uncontrolled, clinically significant neurological, cardiovascular, pulmonary,
             hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality
             which may impact the ability of the participant to participate or potentially confound
             the study results.

          -  Has a known hypersensitivity to any component of the formulation of metformin.

          -  Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol
             abuse within 6 months prior to the screening visit or is unwilling to agree to abstain
             from alcohol and drugs throughout the study.

          -  Currently taking any excluded medication, supplements, or food products, or has taken
             any in the 3 weeks preceding Visit 1. This includes carbonic anhydrase inhibitors and
             the medication topamax.

          -  Has evidence of current cardiovascular, hepatic, hematopoietic disease, renal
             dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma hypoxemia,
             hypertension or allergic skin rash. There is any finding in the participant's medical
             history, physical examination, or safety laboratory tests giving reasonable suspicion
             of a disease that would contraindicate taking metformin or a similar drug in the same
             class, or that might interfere with the conduct of the study. This includes, but is
             not limited to uncontrolled seizure disorders, and cardiac arrhythmias.

          -  History of any surgical intervention known to impact absorption (e.g., bariatric
             surgery or bowel resection).

          -  Compromised renal function at screening as determined by creatinine levels >1.5mg/dL
             and/or creatinine clearance <45mL/min based on Cockcroft-Gault calculation.

          -  Liver dysfunction at screening as evidenced by alanine transaminase (ALT/SGPT) values
             > 2X upper limit of normal or aspartate transaminase (AST/SGOT) values > 3X upper
             limit of normal or total bilirubin > 2X upper limit of normal.

          -  Has donated or lost 450 mL or more of his blood volume (including plasmapheresis), or
             had a transfusion of any blood product within 3 months prior to Day 1.

          -  Has a history of abnormal (clinically significant) electrocardiogram (ECG). Entry of
             any participant with an abnormal (not clinically significant) ECG must be approved,
             and documented by signature by the principal investigator.

          -  Has abnormal Screening or Day 1 vital sign values that suggest a clinically
             significant underlying disease.

          -  Is at risk of suicide, has made a suicide attempt within the last year or has current
             active suicidal ideation. In accordance with previous FDA regulated studies on
             patients with FXS this determination will include asking 3 questions. 1) Has the
             subject made a suicide attempt? 2) Has the subject expressed any (active) suicidal
             thoughts or intent to harm him/herself or others? 3) Has there been a significant
             increase in the severity or frequency of self-injurious behaviors, or harm toward
             others, such that continued safety is a concern?

          -  Laboratory abnormalities in B12, or other common lab parameters that might contribute
             to cognition or participation in study

          -  In the opinion of the investigator or sponsor, the participant is unsuitable for
             inclusion in the study.
Male
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.
Subject must be at most 50 Years

Patient description (medical language): A 15-year-old boy with mild intellectual disability is brought to the office by his parents for a routine physical examination.  The boy is going to a school for students with learning disabilities.  The patient was adopted, and his immunizations are up to date.  Review of the patient's medical records is notable for cytogenetic studies that showed a small gap near the tip of the long arm of the X chromosome, which is consistent with fragile X syndrome, an X-linked disorder. The defect is an unstable expansion of trinucleotide repeats (CGG) in the fragile X mental retardation 1 (FMR1) gene, located on the long arm of the X chromosome. He is not using any medications and vital signs are within normal levels. His blood chemistry analysis as bellow:
Blood Chemistry Value      Normal Range     Patient Value
Glucose                    90-120 mg/dl     95 mg/dl
BUN (Blood Urea Nitrogen)  7-24 mg/dl       10 mg/dl
Creatinine                 0.7-1.4 mg/dl    0.8 mg/dl
Calcium                    8.5-10.5 mg/dl   9 mg/dl
Sodium                     134-143 mEq/L    135 mEq/L
Potassium                  3.5-4.5 mEq/L    3.7 mEq/L
Chloride                   95-108 mEq/L     98 mEq/L
CO2                        20-30 mEq/L      25 mEq/L
Blood pH                   7.38-7.42        7. 39

Patient description (patient's own words): My husband and I brought our 15-year-old son to the clinic for his routine exam. My son is going to school for special needs students. We adopted him a few years ago. His vaccinations are up to date. He already passed some chromosome testing and they found that he has a fragile X syndrome. The doctor told us that it comes from repeats in the fragile X chromosome. My son is not using any medication and his blood pressure temperature and breathing were normal during the exam. He also did a blood test. The results came back and showed that his blood sugar urea creatinine calcium sodium potassium chloride CO2 and blood pH were all within the normal range.

Does the patient match the trial criteria? Contradiction