Cystic Fibrosis-related Diabetes, Pancreatic Insufficiency
Conditions
Brief summary
This study is designed to determine the pharmacokinetic and pharmacodynamic response of dorzagliatin 50 mg twice daily following 7-day administration in individuals with pancreatic insufficient cystic fibrosis and abnormal glucose tolerance when compared to randomized, double-blind 7-day administration of placebo in a cross-over fashion. We hypothesize that dorzagliatin administration will result in significant drug concentrations and improved glucose tolerance, early-phase insulin secretion, glucagon suppression, and hepatic glycogen storage assessed during a standardized mixed-meal tolerance test.
Interventions
DRUGDorzagliatin
Randomized, double-blind, cross-over study of Dorzagliatin 50 mg orally twice daily for 7 days compared to matched-placebo orally twice daily for 7 days.
DRUGPlacebo
Randomized, double-blind, cross-over study of Dorzagliatin 50 mg orally twice daily for 7 days compared to matched-placebo orally twice daily for 7 days.
Sponsors
Michael R. Rickels, MD, MS
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of signed and dated informed consent form. 2. Stated willingness to comply with all study procedures and availability for the duration of the study. 3. Male or female, aged ≥18 years on date of consent. 4. Confirmed diagnosis of CF, defined by positive sweat test or CFTR mutation analysis according to CFF diagnostic criteria. 5. Pancreatic insufficiency defined by clinical requirement for pancreatic enzyme replacement. 6. Abnormal glucose tolerance defined by OGTT criteria for EGI, IGT, or CFRD, or diagnosed CFRD. 7. There will be no restriction on enrollment of individuals with CFRD but without fasting hyperglycemia (fasting hyperglycemia is defined as fasting glucose ≥126 mg/dL) a. Individuals with CFRD and fasting hyperglycemia (defined as above or by the use of basal insulin therapy) must also have a HbA1c ≤8% and a random (non-fasting) C- peptide ≥1.2 ng/mL \[15\]. 8. For females of reproductive potential: use of highly effective contraception method for the during of study participation; oral contraceptives, intra-uterine devices, Norplant®, Depo- Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
Exclusion criteria
1. Established diagnosis of non-CF diabetes (e.g. type 1 diabetes). 2. Pregnancy or lactation; a negative urine pregnancy test will be required at enrollment. 3. Pulmonary exacerbation requiring IV antibiotics or systemic glucocorticoids within 4 weeks prior to randomization. 4. Treatment with either CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, indinavir, ritonavir, saquinavir, telithromycin, boceprevir, nelfinavir, telaprevir, conivaptan, nefazodone, etc.) or inducers (e.g. phenobarbital, other barbiturates, carbamazepine, phenytoin, rifampicin, dexamethasone, etc.). 5. Use of herbal remedies, including St. John's Wort within 14 days prior to dosing. 6. Change in CFTR modulator therapy in the previous 3 months. 7. History of clinically symptomatic pancreatitis within the last year. 8. Prior lung, liver or another solid organ transplant. 9. Abnormal kidney function: creatinine \>2x upper limit of normal (ULN) or potassium \>5.5mEq/L on non-hemolyzed specimen. 10. Abnormal liver function: persistent elevation of liver function tests \>2.0 times ULN. 11. Uncontrolled hyperlipidemia: triglycerides \>500 or cholesterol \>250 mg/dl. 12. Hyperuricemia: serum uric acid \>1.5 times ULN. 13. Anemia: hemoglobin \<10 g/dL. 14. History of any illness or condition that, in the opinion of the investigator might confound the results of the study or pose an additional risk to the subject.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Drug concentrations (PK; Cmax) | 2 months | Assessed by the peak glucose during a standardized mixed-meal tolerance test following 7-day administration of study drug |
| Glucose tolerance (PD) | 2 months | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Early-phase insulin secretion | 2 months | Assessed by insulin secretory rate and |
| Glucagon suppression | 2 months | Glucagon incremental area-under-the-curve (iAUC) analyses during the mixed-meal tolerance test following 7-day administration of study drug. iAUC analyses for GLP-1 and GIP will be assessed as potential effect modifiers. |
Countries
United States
Contacts
CONTACTPaola Alvarado, MSCR
PRINCIPAL_INVESTIGATORMichael R Rickels, MD, MS
University of Pennsylvania
Outcome results
None listed