Clinical trial NCT06995651: Dorzagliatin in Pancreatic Insufficient Cystic Fibrosis
Official title: Pharmacokinetic and Pharmacodynamic Effects of Dorzagliatin in Pancreatic Insufficient-Cystic Fibrosis: A Randomized Double-blind, Cross-over Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Pancreatic Insufficiency
Cystic Fibrosis-related Diabetes
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
First posted: 2025-05-29
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This study is designed to determine the pharmacokinetic and pharmacodynamic response of dorzagliatin 75 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Drug concentrations (PK; Cmax)
timeFrame: 2 months
measure: Glucose tolerance (PD)
timeFrame: 2 months
Secondary outcomes:
measure: Early-phase insulin secretion
timeFrame: 2 months
measure: Glucagon suppression
timeFrame: 2 months
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Hospital of University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania Center for Human Phenomic Science (CHPS)
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Michael R Rickels, MD, MS
role: PRINCIPAL_INVESTIGATOR
References: